Tumor metabolism regulating chemosensitivity in ovarian cancer

Copyright: Han et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

Elevated metabolism is a key hallmark of multiple cancers, serving to fulfill high anabolic demands. Ovarian cancer (OVCA) is the fifth leading cause of cancer deaths in women with a high mortality rate (45%). Chemoresistance is a major hurdle for OVCA treatment. Although substantial evidence suggests that metabolic reprogramming contributes to anti-apoptosis and the metastasis of multiple cancers, the link between tumor metabolism and chemoresistance in OVCA remains unknown. While clinical trials targeting metabolic reprogramming alone have been met with limited success, the synergistic effect of inhibiting tumor-specific metabolism with traditional chemotherapy warrants further examination, particularly in OVCA. This review summarizes the role of key glycolytic enzymes and other metabolic synthesis pathways in the progression of cancer and chemoresistance in OVCA. Within this context, mitochondrial dynamics (fission, fusion and cristae structure) are addressed regarding their roles in controlling metabolism and apoptosis, closely associated with chemosensitivity. The roles of multiple key oncogenes (Akt, HIF-1α) and tumor suppressors (p53, PTEN) in metabolic regulation are also described. Next, this review summarizes recent research of metabolism and future direction. Finally, we examine clinical drugs and inhibitors to target glycolytic metabolism, as well as the rationale for such strategies as potential therapeutics to overcome chemoresistant OVCA.

INTRODUCTION

Ovarian Cancer (OVCA) is the fifth leading cause of cancer deaths in women and has a high mortality rate (30-50%) [1, 2]. Late diagnosis and the development of chemoresistance are major hurdles to successful therapy. Due to non-specific clinical symptoms and the absence of early biomarkers, OVCA is usually diagnosed in advanced stages. Epithelial OVCA accounts for more than 90% of OVCA incidences and has the highest mortality rates [3]. Within epithelial OVCA, high-grade serous is most frequently found (70%) among different sub-types (high-grade, low-grade, endometroid, clear cell, and mucinous)[4]. The standard treatment of OVCA is debulking surgery followed by chemotherapy, but 70% of patients in advanced stage experience chemoresistance or relapse within 15 months following treatment [5].

Cis-diamminedichloroplatinum (II) (Cisplatin, CDDP) and its analogues (e.g., Carboplatin and Oxaliplatin) are commonly used platinum containing anti-cancer drugs as DNA damaging agents in OVCA. The underlying mechanisms of chemoresistance are multifactorial, partly due to defects in apoptosis, dysregulation of an oncogene, defects in tumor suppressors, and increased metabolism [6, 7]. The master tumor suppressor p53 is responsible for apoptosis of cancer cells and is critical to the chemoresponsiveness of OVCA [8, 9].

TP53 mutations occur in 70% cases of OVCA and in more than 90% cases in high-grade serous epithelial OVCA [10], and is closely associated with chemoresistance [11]. Understanding in-depth metabolic and molecular mechanisms are required in the pursuit for effective therapeutic targets to overcome chemoresistant OVCA. Metabolic reprogramming enables cancer cells to fulfill their high proliferation and survival potentials [12]. Since Otto Warburg proposed a high rate of aerobic glycolysis in cancer cells (Warburg effect) in 1923 [13, 14], the unique metabolic character of cancer cells has been intensely investigated as a target for cancer therapy. The Warburg effect specifically proposes that glycolysis is main metabolic pathway for ATP generation and oxidative phosphorylation (OXPHOS) is impaired in cancer cells; however, recent research has demonstrated that both pathways are relatively elevated in cancer cells compared to normal cells [12, 15]. Moreover, it may be that the ability of cancer cells to switch between energy substrates and metabolic pathways (termed bioenergetic flexibility) is associated with poor prognosis, including metastasis [16, 17]. Glycolysis works as precursor pathway, since its metabolites and products are required for downstream pathways including: the tricarboxylic acid (TCA) cycle and OXPHOS; pentose phosphate pathway (PPP) for ribonucleotide synthesis and NADPH; glycosylation and gluconeogenesis; amino acid biosynthesis, and fatty acid synthesis [12, 18]. In addition to glycolysis, the PPP pathway is highly elevated in cancer [19, 20], providing anabolic substrates for cancer growth and reductive intermediates (NADPH) for glutathione synthesis and protection from oxidative damage.

Fatty acid metabolism is similarly altered in cancer. Unsaturated lipids are increased in OVCA [21, 22], which induces stemness, whereas lipid desaturation impairs cancer stemness and tumor initiation [22]. Cellular glycogen accumulation is observed as a feature of clear cell, a sub-type of epithelial OVCA, which frequently develops chemoresistance [23]. Also, glycogen accumulation is elevated in hypoxic conditions, a core component of the solid tumor microenvironment [23, 24]. These findings suggest that specific metabolic phenotypes enhance chemoresistance in OVCA

However, it remains unclear whether metabolic reprogramming in cancer is associated with chemoresistance and what therapeutic approaches could modulate metabolic phenotypes associated with chemoresistance of OVCA (Figure. 1). In this review, we discuss: 1) the cellular and molecular mechanisms involved in metabolic reprogramming; 2) the influence of metabolism on apoptosis and the related functions of mitochondria; 3) whether and how oncogenes/tumor suppressors regulate the role of key glycolysis enzymes; 4) future strategies for targeting metabolism in cancer treatment, including combining such therapies with traditional chemotherapeutics; and lastly, 5) the importance of tumor microenvironment and potential novel metabolic strategies.

The role of glycolytic metabolism in chemo-resistance

Accelerated glycolysis is a key hallmark of tumorigenesis [13, 25, 26]. Glycolysis is the first metabolic pathway converting glucose to pyruvate. Beyond their metabolic functions, key glycolytic enzymes have been shown to enhance the survival and progression of tumors associated with drug resistance (Figure. 2). Metabolic adaptation of excessive glycolysis in cancer is mediated by hyperactive glycolytic enzymes, and this is primarily due to dysregulation of tumor suppressors or activation of oncogenes [27]. Glucose transporters

Glucose transporters (GLUTs) are a large group of membrane transport proteins that facilitate the transport of glucose over a plasma membrane [28]. There are 14 identified GLUTs (SCL2A1 to SCL2A14). Among them, GLUT1 has been identified as a hypoxic marker and plays the critical role in the Warburg effect [29]. In cancer cells, GLUT1 is highly expressed and facilitates metastasis of tumor and poor prognosis in multiple cancers including lung, stomach, breast, and kidney [29, 30]. High level of GLUT1 expression is observed in membrane of high grade serous OVCA, whereas GLUT1 expression is negatively correlated with fasting glucose concentration, explaining its glucose uptalking [31]. In OVCA, by modulating GLUT1 membrane trafficking, phytochemicals such as resveratrol decreases glycolysis and induces apoptosis [32]. Hexokinase II

Hexokinase (HK) is the enzyme involved in the first committed and irreversible step in glycolysis, converting glucose to glucose-6-phosphate (G6P). There are five hexokinase isoforms including recently discovered HKV (HKI, II, III, IV, and V) [33]. HKI to HKII have high substrate affinity, while HKIV has low glucose affinity and serves as an important glucose sensor (e.g., to control β-cell insulin release). A fifth hexokinase as novel isoform was recently found, and it remains to be further explored [33]. HKI and HKII are found in many cellular compartments, including being bound to the outer mitochondrial membrane (OMM), and localized within mitochondria [34]. Both HKI and HKII are inhibited by G6P, its catalytic product via feedback inhibition [14]. HKII, a predominant isoform in insulin sensitive tissues (adipose, skeletal, and cardiac muscles), is highly expressed in multiple tumors [35]. Recent research demonstrates that HKII is highly associated with tumorigenesis and cancer cell survival [26, 36]. In mouse models, deletion of HKII significantly decreased tumor burden and prolonged survival, suggesting that HKII is a critical factor involved in tumor progression [37]. Inhibition of HKII restored normal glycolysis and OXPHOS pathway as well as mitochondrial biogenesis in glioblastoma [38]. HKII depletion also increased intrinsic apoptosis by increased mitochondrial permeability in chemoresistant brain cancer cells [38]. Lysophosphatidic acid (LPA), a lipid growth factor and G protein-coupled receptor (GPCR) ligand are significantly increased in OVCA, triggering the activation of HIF1α and inducing GLUT1 and HKII, thus shifting cells towards a glycolytic metabolism [39]. Zhang et al. have demonstrated that HKII contributes to chemoresistance by enhancing CDDP-induced ERK1/2 phosphorylation and autophagy [40].Phosphofructokinase 1 (PFK1)

Phosphofructokinase (PFK) 1 is responsible for converting fructose-6-phosphate (F6P) to fructose 1,6 bisphosphate (F 1,6 BP), the second irreversible step in glycolysis [41, 42]. Somatic mutation of PFK and altered structure promote altered glycolytic flux in cancer [43]. The most potent allosteric activator of PFK is fructose 2,6 bisphosphate (F 2,6 BP) and its synthesis and degradation depend on the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB) [44]. PFKFBs phosphorylate fructose 6-phosphate (F6P) to fructose-2,6-bisphosphate (F 2,6 BP), which in turn activates PFK1, forwarding glycolytic flux to lactate. Among the five PFKFB isoenzymes (PFKFB 1-4, and TIGAR), PFKFB3 has the highest kinase/phosphate activity ratio, leading to elevated F-2,6-BPase and resulting in high glycolysis rate. PFKFB3 promotes cell cycle progression and suppresses apoptosis by facilitating cyclin dependent kinase (Cdk)-induced degradation of p27, a key apoptotic activator [41]. Its product, F 2,6 BP is shown to be highly expressed in ovarian and breast cancers [44]. Conversely, PFKFB4 depletion increased apoptosis and the production of reactive oxygen species (ROS) in mitotically arrested cells. It also significantly enhanced mitotic cell death in OVCA with paclitaxel treatment [45]. Pyruvate kinase

Pyruvate kinase (PK) catalyzes the last irreversible reaction of glycolysis, converting phosphoenolpyruvate to pyruvate. Two distinct PK genes, PKL/R (in liver and red blood cells) and PKM2 (in muscle) encode four PK isoforms: PKM1, PKM2, PKR, and PKL. Among them, PKM2 is allosterically regulated by various metabolites [46, 47]. The activity of PKM2 enables cancer cells to adapt to altered tumor metabolic conditions. Phosphorylated PKM2 dimers stimulate a high rate of nucleotide and amino acid biosynthesis, while indirectly sustaining the Warburg effect [47]. Depletion of PKM2 in a breast cancer mouse xenograft model showed a reversal of the Warburg effect and inhibits tumor growth [48]. High expression of PKM2 is found in malignant OVCA, suggesting its late stage detection role of poor prognosis [49]. The association of PKM2 with tumorigenesis depends on the type of cancer, as the suppression of PKM2 did not show anti-tumor activity in breast and colon cancer, but did in leukemia [50, 51].Lactate dehydrogenase

Lactate dehydrogenase (LDH) catalyzes the interconversion of pyruvate and lactate, and of NADH and NAD+. Four LDH isozymes exist (LDH-A, LDH-B, LDH-C, and LDH-D), with LDH-A being predominantly expressed in the majority of tissues. Elevated levels of LDH-A are associated with multiple solid tumors and poor prognosis of cancer [52]. As LDH-A promotes the reduction of pyruvate to lactate for NADH production, whereas LDH-B favors the reverse reaction; LDH-A is a key enzyme involved in the Warburg effect. Depletion of LDH-A in tumor cells and in mice reduces tumor growth [53]. Recent research demonstrates that LDH supports enhanced rates of oxidative metabolism in tumors e.g., TCA cycle activity [54, 55]. Moreover, excessive activity of LDH in glycolysis can lead to local acidification of the tumor microenvironment, a favorable condition for tumor invasion and metastasis [56, 57]. High level of LDH is observed in serum and peritoneal fluid from OVCA patients compared with that of benign tumor, suggesting its possible role as potential prognostic biomarker [58, 59]. Lactate, the end product of LDH, a key gluconeogenic precursor, is moved intracellularly (within a cell) and intercellularly (between cells) (Lactate shuttle) via monocarboxylate transporters (MCT)1 and MCT4, proposed by Brooks et. Al [60]. This notion is also supported by the evidence that high expression of MCT1 promotes the CDDP resistance by antagonizing the effect of first apoptosis of signal receptor (Fas) in epithelial OVCA [61]. High levels of lactate, as key elements for energy source and tumorigenesis, have been observed along with subsequent active glycolysis in many cancers [62].

The influence of elevated glycolysis on mitochondrial-mediated apoptosis in cancer

The role of mitochondrial HKII for cell survival

Intrinsic (mitochondria-mediated) apoptosis is initiated by the loss of mitochondrial membrane potential, increased mitochondrial outer membrane permeabilization (MOMP), and the subsequent release of mitochondrial death proteins including cytochrome c [63]. In addition to its role in glycolysis, HKII is involved in protecting mitochondria and the suppression of intrinsic apoptosis [64] (Figure.3), whereas its depletion of HKII enhances apoptosis and sensitivity to external stimuli. Ectopic expression of HKII protects lung cancer cells and renal epithelial cells from oxidative injury or cell death [65, 66]. Depletion of HKII in human HCC cells enforces metabolic pathway toward oxidative phosphorylation through maintaining TCA flux, thus facilitating cell death and inhibiting tumorigenesis [67].

In line with its role in regulating MOMP, HKI and HKII can bind to voltage-dependent anion channel 1 (VDAC1), a likely component of the mitochondrial permeability transition pore (mPTP) [26, 68]. Approximately 80% of HKII is localized with mitochondria in cancer cells [34]. Accumulating studies showed that Mito-HKII enhances tight coupling of glucose phosphorylation to mitochondrial ATP generation [69, 70]. Hay et al. showed that ectopic expression of mitochondrial binding-deficient HKII failed to restore cell proliferation and tumorigenesis, emphasizing pivotal role of mitochondria-bound HKII [67]. Mitochondrial Ca²⁺ overload and ROS induce the opening of mPTP and consequent rupture. Mito-HKII provides cellular protection against this Ca²⁺ overload and mPTP opening [36]. The interaction of HKII with Bcl-2 members also affects apoptotic processes, particularly the execution of intrinsic apoptosis. Some anti-apoptotic molecules of Bcl-2 family (e.g., Bcl-2 and Bcl-XL) stay in the OMM, whereas pro-apoptotic members (Bad, Bax, and Bid) are translocated from the cytosol to the OMM upon initiation of apoptotic signaling [71, 72]. In mitochondrial-mediated cell death, activated Bax/Bak forms a pore at the OMM, induces MOMP, and results in the release of apoptotic factors such as cytochrome c from the inter-membrane space [72], which then accelerates the opening of VDAC [73]. Conversely, anti-apoptotic Bcl-2 family members, such as Bcl-XL interact with VDAC, inhibiting cytochrome c release by modulating OMM integrity or MOMP [71, 74]. Mito-HKII inhibits binding of Bax to Bcl-2 through competitive inhibition and antagonizes truncated Bid (tBid)-mediated apoptosis [75, 76]. Upon cell stress (e.g., glucose restriction or treatment with Metformin, Clotrimazole, Flavonoid-429, 2-DG, or 3-Bromopyruvate) HKII is detached from VDAC [77-80], inducing dysregulation of mitochondria by opening the mPTP, increasing the MOMP, and subsequent inducing of mitochondrial-mediated apoptosis [75, 81]. HKII dissociation from mitochondria using an artificial peptide also was shown to induce apoptosis without changing mitochondrial membrane potential, ROS production, or oxidative phosphorylation [79]. This suggests that detachment of HKII from mitochondria is critical for intrinsic apoptosis. However, the molecular mechanism of HKII detachment remains to be elucidated.

Cristae structural alterations, and changes in the ultrastructure of the inner mitochondrial membrane compartments, also significantly contribute to apoptotic signaling [82, 83]. Optic Atrophy 1 (OPA1) is a pro-fusion dynamin-related protein in the inner mitochondrial membrane that regulates cristae structure. OPA1 associates with itself to form oligomers, which act to maintain narrow cristae and narrow cristae junctions. However, Bax/Bak activation can disrupt OPA1 oligomerization, thereby widening cristae, and aiding in the release of pro-apoptotic factors and ultimately inducing apoptosis [83]. We observed that CDDP induced OPA1 processing and that intact OPA1 is associated with chemoresistance [84, 85]. However, it remains unknown if and how Mito-HKII is involved in Bax - Opa1 interaction and how this affects OPA1 oligomerization [82] and cristae structure.

In addition, the role of uncoupling proteins (UCPs) in modulating mitochondrial HKII has been demonstrated. The uncoupling proteins (UCPs) are mitochondrial anion transporters of the inner mitochondrial membrane and control the coupling efficiency of oxidative phosphorylation, and indirectly also ROS emission [86, 87]. UCP3 contributes to the role of HKII in aerobic glycolysis. Genetic knockout or inhibition of UCP3 decreased mitochondrial-bound HKII and increased mitochondrial ROS emission, suggesting a role of UCP3 in HKII mitochondrial association [88]. Moreover, UCP2 in tumor cells is associated with decreased ROS emission and chemoresistance [89]. It remains to be determined if UCP2 interacts with HKII, as UCP3 does. The role of mitochondrial fission/fusion in metabolic reprogramming of cancer

Mitochondria are highly dynamic organelles regulated by fission and fusion events and, as described above, cristae undergo important ultrastructural changes. Indeed, mitochondrial dynamism plays essential roles in fundamental cellular processes and metabolism, and changes in mitochondrial dynamics have been linked to cancer [90, 91]. Mitochondrial fusion is regulated by the dynamin GTPases, Mitofusin 1 and 2 (Mfn1, Mfn2) and OPA1, while mitochondrial fission is regulated by dynamin-related protein (Drp1) and recruitment/activation factors (Mff, Fis1, MiD49 , and Mid50) [92]. Mitochondrial fusion is additionally correlated with altered cristae structure, enhanced assembly of respiratory super-complexes and ATP synthase assembly, often shifting cells from glycolysis to OXPHOS [93, 94]. The role of mitochondrial fission/fusion in the regulation of apoptosis and cell survival remains controversial. In OVCA cells, we observed significant higher level of mitochondrial fusion in chemoresistant cells than in their chemosensitive counter parts [84, 95]. CDDP increased significant mitochondrial fission in chemosensitive cells, but not in chemoresistant cells. Piceatannol, a metabolite of functional food compound in red wine, sensitized OVCA to CDDP in vitro and in vivo, by inducing dephosphorylation of mitochondrial fusion protein, Drp1 at site of ser 637, and promoting mitochondrial fission and apoptosis [96]. This indicates that higher proportion of tubular network in mitochondria harboring chemoresistance cells are closely related to anti-apoptosis and cell survival.

Few studies have reported the mitochondrial dynamics and energy metabolism in OVCA. Generally, through either enhanced mitochondrial fission, or decreased mitochondrial fusion, cancer cells have increased mitochondrial fragmentation, which has a functional role to promote glycolysis for energy production over OXPHOS [97]. Pro-survival factor, Survivin (BIRC5) overexpression leads to mitochondrial fragmentation through increased mitochondrial fission, shifting energy production toward glycolysis [98, 99]. Also, the inhibition of glycolysis attenuates the anti-apoptotic action of Survivin. However, cancer cells can adapt their mitochondrial structure in response to metabolic challenges similar to non-cancerous cells [97, 100, 101]. These reports demonstrate that cancer cells adapt to stressful energy conditions by modulating mitochondrial morphologies and functions generally associated with increased glycolysis. Mitochondrial biogenesis and glycolysis metabolism

To maintain energy metabolism and function upon external stress, mitochondrial autophagy (mitophagy) and mitochondrial biogenesis are cooperatively required to regulate cellular homeostasis and survival [102]. Intact mitochondrial function and mitochondrial biogenesis are indeed required for survival of cancer cells [103]. Cancer cells respond to changes in glucose and other nutrient sources by altering mitochondrial biogenesis [102, 104]. Also, the key oncogenic transcription factor c-MYC has been shown to facilitate glycolysis and mitochondrial biogenesis with associated increases in ATP production [105, 106]. ROS and glycolytic metabolism

Aberrant high levels of ROS generation are often associated with increase in antioxidant defenses in cancer cells [107]. ROS are potentially damaging byproducts of mitochondrial oxidative metabolism, but also function as second messengers in the transduction of extracellular signals that control cellular proliferation and cell cycle progression [108]. As a master regulator of ROS and mitochondrial energy metabolism, peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α) is partly responsible for this detoxification [16]. Through stimulating bioenergetic potential, PGC-1α promotes migration and invasion of breast cancer and facilitates chemoresistance [17]. Other transcription factors, nuclear respiratory factors (NRF1 and NRF2), the estrogen-related receptors (ERR-α, -β and -γ) and the nuclear factor erythroid 2-related factor 2 (NRF2/NFE2L2) act as master regulators of anti-oxidants [109]. In spheroid OVCA cell cultures, ROS induced high expression of PGC1α, a phenomenon associated with metastasis, stemness, and chemoresistance [110]. Also, Nrf2 is overexpressed in clear cell ovarian carcinoma exhibiting high glycolytic phenotype, and high nuclear expression of Nrf2 is associated with poor prognosis of OVCA patients [111, 112]. Glutathione (GSH), an important antioxidant, is critical for modulating apoptosis. In OVCA, GSH is inversely associated with chemoresistance and levels of GSH are 15-50 fold higher in chemosensitive cells than chemoresistant cells [113]. Mitochondrial GSH protects cells from ROS during mitochondrial respiration [114, 115]. Moreover, NADPH produced by the PPP is required for the generation of reduced GSH [116]. Hence, GSH functions as metabolic link between PPP and ROS balance.

Regulatory mechanisms of glycolytic metabolism in ovarian cancer

Aberrant activation of glycolysis by oncogenes

Accumulating evidence suggests that multiple tumor suppressor/oncogenes affect glucose metabolism [12, 117]. The phosphoinositide-3 kinase (PI3K)/Akt axis is a key oncogenic cell signaling pathway in cell survival and tumor progression, and may promote glycolytic reprogramming. For example, acute insulin treatment leads to the trafficking of glucose transporter in a PI3K /Akt-dependent manner [118]. PI3K is a phospholipid kinase that phosphorylates the 3′ hydroxyl (OH) group of the inositol ring of phosphoinositide lipids [119]. PI3K phosphorylates the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP₂) to form phosphatidylinositol 3,4,5-triphosphate (PIP₃), whereas this process is regulated by tumor suppressors phosphatase and tensin homolog (PTEN) to dephosphorylate PIP3 [120]. Akt is serine/threonine kinase and is highly upregulated in cancer cells [121]. Akt is activated by its recruitment to the plasma membrane by PIP3, followed by phosphorylation of Thr³⁰⁸ and Ser⁴⁷³ by PDK1 [122].

Akt promotes glycolysis, suppresses apoptosis, and elicits cell survival via multiple mechanisms [35, 123, 124]. PI3K pathway activation or mutational changes in genetic and function were common in OVCA [125]. Effect of inhibition of AKT depends on genetic heterogeneity of cancer. Inhibition of AKT1 selectively caused cancer growth in subset of OVCA cells lines, but not applied to all of OVCA subset, due to high expression of other AKT isoforms [126, 127]. Akt enhances mitochondrial HKII activity and in turn OMM stability, thereby increasing its anti-apoptotic action. Akt directly phosphorylates HKII at the consensus binding site of (RARQKT*) Thr 473. Phosphorylated-HKII (p-HKII) is more stably associated with mitochondria, by inhibiting opening of mPTP [123, 128]. Akt facilitates binding of BcL-XL and HKII to VDAC in OMM. Apoptosis induction and mPTP formation by Bax/Bak are prevented, largely due to pre-occupied Bax binding site by HKII for OMM permeability [36, 124]. Also, Akt activates PFK1 by the phosphorylation and activation of PFKFB2 [129]. In breast cancer, FV-429 inhibits glycolysis by attenuating Akt-mediated phosphorylation of HKII, resulting in apoptotic induction [78]. As oncogenes, KRAS and BRAF activate Akt and mutation of KRAS/BRAF enhance the expression and plasma membrane trafficking of GLUT1 [130-132]. Still, it remains unclear how the interplay of Akt/p53 affects the HKII-mediated glycolysis and other metabolic processes in cancer.

c-MYC (v-myc avian myelocytomatosis viral oncogene homolog) is an oncogene and transcription factor that regulates multiple genes involved in cell proliferation, metabolism, and apoptosis [133]. Constitutive activation of c-MYC is frequently found in human cancer [134]. In OVCA, protein expression of c-MYC is higher in chemosresistant cells compared with its counterpart sensitive cells [135, 136]. High c-MYC expression is also associated with decreased overall survival and disease free survival rate [136]. c-MYC contributes to chemoresistance of cancer in part by controlling metabolism [137]. c-MYC binds and activates the promoters of key metabolic enzymes including GLUT1, HKII, PFK, and enolase 1 (ENO1), leading to an activation of the glycolysis pathway [138-140]. In addition, c-MYC cooperates with HIF-1α to promote HKII and PDKI, again shifting metabolic pathway to glycolysis [137].

mTOR is a serine/threonine kinase involved in promoting energy metabolism, cell growth and proliferation. Elevated mTOR suppresses induction of autophagy and frequently leads to the development of tumors [35, 117]. mTOR is composed of two distinct functional complexes, mTOR complex 1 and 2 (mTORC1 and mTORC2), with their respective defining components Raptor and Rictor [52]. Akt activates mTOR, promoting anabolic metabolism and fatty acid synthesis, whereas AMPK represses mTOR, leading to catabolic energy production and fatty acid oxidation. In response to glucose deprivation, HKII can bind to mTORC1 by its TOS motif, decreasing TORC1 activity and positively regulate autophagy [141]. Under glucose depletion, inhibition of HKII is attenuated, while overexpression of HKII elevates glucose deprivation-induced autophagy [35, 141]. This indicate that cells increase their adaptability and survival by mTOR-HKII interaction under varied energy conditions.

MicroRNAs (miRNAs) are small, non-coding RNAs and post-transcriptional inhibitory regulators of gene expression. As a tumor suppressor miRNA, miR-143 downregulates HKII, whereas oncogenic miR-155 upregulates HKII expression [142]. Overall, key oncogenes promote glycolysis metabolism and cell survival, whereas tumor suppressors regulate it in OVCA, incurring its responsiveness to chemotherapy. Regulation of glycolysis by p53

p53, key tumor suppressor is involved in the regulation of cellular proliferation, apoptosis, and metabolism [52]. p53 elicits its apoptotic action via transcription-dependent and -independent mechanisms [9]. Our lab has demonstrated that activation of functional p53 signaling is required for apoptosis in response to chemotherapy such as CDDP [7, 143]. In addition to its fundamental role in apoptosis, p53 is shown to negatively regulate glycolysis [144], as its mutation may lead to the reliance on glycolysis of cancer cells [10]. Moreover, co-deletion of p53/PTEN in prostate cancer can further increase HKII levels. PTEN deletion increase HKII mRNA translation via activation of the AKT-mTOR-4EBP1 pathway, whereas p53 loss enhances HKII mRNA stability by inhibiting miR-143 biogenesis [145]. p53 plays a critical role in maintaining mitochondrial integrity and function, potentially through modulating SCO2 (the synthesis of cytochrome c oxidase protein) and cytochrome oxidase II (COX II) [146, 147]. SCO2 is required for the oxidative phosphorylation, mitochondrial respiration, and the assembly of the mitochondrial complex with COX II. Therefore, depletion of p53 impairs mitochondrial structure and respiration, shifting cells toward glycolytic metabolism. p53 can also induce glycolysis and apoptosis regulator (TIGAR)[148]. TIGAR has a dual function in regulating glycolysis to maintain homeostatic balance system in the cell. TIGAR leads to the accumulated production of G6P, preventing glycolysis. However, under hypoxic conditions, TIGAR is translocated to mitochondria and binds to HKII, decreasing ROS, promoting glycolysis, and providing cell protection [148, 149]. Mutant p53 promotes the plasma membrane trafficking of GLUT1 via Rho-associated protein kinase (ROCK) signalling [150]. Despite p53’s regulatory role in metabolism, detailed molecular and temporal mechanisms remain to be further elucidated.

Targeting metabolism for cancer therapy

Current status of therapeutic approaches in targeting metabolism

For the numerous aforementioned reasons, targeting glucose metabolism has been considered as a promising therapeutic strategy. However, side effects and barriers to effective treatments have led to several unsuccessful clinical trials (Table. 1).

2-Deoxyglucose (2-DG), lonidamine (LND), and 3-Bromopyruvate (3-BP) are used as hexokinase inhibitors. 2-DG, a glucose analogue, is a competitive HK inhibitor. Researches under in vitro & in vivo conditions demonstrate that concomitant use of 2-DG with inhibitors of lysosomal permeabilization increased its anti-tumor action, inducing mitochondrial damage and necrotic cell death [151]. As well, cotreatment of 2-DG with the PPARα agonist, fenofibrate (FF) leads to cancer cell death by inducing ER stress [152]. Despite these promising results, 2-DG clinical trials were stopped in phase I, since 2-DG resulted in intolerable hypoglycemia and reduced white blood cell counts in leukemia patients [153]. Also, it is toxic when given concurrently with radio therapy in glioma patients [154]. With regards to safety and efficacy, minimal concentration of 2-DG with use of concomitant chemotherapeutic agent or other glucose analog inhibitors with better specificity could be considered.

Given that HKII has variable isoforms and HKI is also highly expressed in normal cells, target specificity is of ultimate importance for safety and efficacy. Other drugs such as 3-Bromo pyruvate and methyl jasmonate, which are known to specifically detach HKII from VDAC of mitochondria, showed anti-neoplastic effects in vitro and in vivo mouse tumor models [155, 156]. These drugs have been shown to facilitate mitochondria-mediated apoptosis, whereas their targets cover a broad spectrum, including inhibition of glyceraldehyde -3-phosphate dehydrogenase (GAPDH) and LDHA.

Lonidamine (LND, indazole-3-carboxylic acid), inhibits HKII and aerobic glycolysis in hypoxic conditions. Since its combined therapy with temozolomide showed anti-tumor effects in brain cancer, clinical trials for combinational approaches are underway [64]. In advanced OVCA, LND has been shown to be active and tolerable in phase II clinical trial when combined with CDDP and Paclitaxel [157]. Though the results are promising, the possible application of LND in treating chemoresistant OVCA requires further investigation.

3-(3-Pyrinidyl)-1-(4-Pyrinidyl)-2-propane-1-one (3-PO) inhibits PKFB3 family of enzymes which regulate F2,6 BP and the activity of PFK1, a rate-limiting step of glycolysis. 3-PO shows a suppressive effect in glycolytic flux and growth of cancer cells in vitro and in vivo [158]. 3-PO and its derivatives are currently in clinical trials for their efficacy and safety.

Dichloroacetate (DCA) was originally used for hereditary lactic acidosis [159, 160]; however, DCA is also considered as an anti-cancer drug that targets metabolism. DCA inhibits PDK1, thereby stimulating the activity of PDH, and shifting cells from glycolysis and lactate product to mitochondrial respiration. DCA treatment induced apoptosis in endometrioid cancer [159]. Combined treatment with DCA and metformin showed a synergistic effect in the suppression of OVCA [161]. Also, DCA treatment with the anti-angiogenesis agent, bevacizumab (Avastin), enhanced anti-tumor effects in brain cancer through reversing hypoxic adaptation [162]. Considering that bevacizumab was recently approved (2016) for recurrent platinum-sensitive OVCA, concomitant use of bevacizumab with DCA may broaden its scope to chemoresistant OVCA [162]. Clinically, this drug has recently shown successful efficacy as durable remission for four years in glioblastoma and resistant non-Hodgkin lymphoma, but further clinical studies need to be conducted in other solid tumors in combinational therapy [163, 164].

In addition, repurposing Metformin, the first-line medication for type 2 diabetes, has gained immense interest as potential cancer treatments [165]. Metformin inhibits mitochondrial complex I and targeting mitochondrial Bcl-2 family of anti-apoptotic proteins in cancers. Metformin has also been shown to directly inhibit HKI and HKII by mimicking of its product, G6P as a competitive inhibitor [166]. Accumulating evidence supports its anti-tumor activity [160, 161, 167, 168]. Metformin antagonizes proliferation of cancer cells by suppressing flow of glucose- and glutamine-derived metabolic intermediates, leading to decreased citrate production and lipid biosynthesis [169]. Recent research demonstrates that its anti-tumor activity is increased when Metformin is used along with p53 stabilizers [168]. Currently, metformin and combined chemotherapy (cisplatin and carboplatin) are in initial phase (recruiting patients) of clinical trial in multiple solid tumors, including OVCA [165], worldwide (USA, UK, Netherland, Australia, and Norway) [170].

AT-101 (Gossypol) is used as a Bcl-XL inhibitor and is also shown to target lactate dehydrogenase. It is currently in phase I clinical trial as combined therapy with other apoptosis-inducing chemotherapy agents (Docetaxel, Cisplatin, and Carboplatin) in relapsed leukemia and laryngeal cancer. Though Imatinib (Gleevec) has never been in clinical trial covering the spectrum of targeting metabolism, it has recently been showed to also inhibit glycolysis activity [160]. Still, implementation of pre-approved drug or broadening the indications of current drugs targeting metabolism is an on-going process. Based on the outcome of previous clinical trials, specifically targeting metabolism seems justified, but the promising synergistic anti-tumor effects with conventional chemotherapy seem promising. As adjuvant chemotherapy, these strategies should be implemented to maximize synergistic effect to current chemotherapeutic agents such as paclitaxel and carboplatin.

In addition to chemical inhibitors of tumor metabolism, restriction of nutrition has been considered as a plausible option. The ketogenic diet (low carbohydrate, high fat and adequate protein) under certain settings may suppress tumor growth and increase chemosensitivity [171, 172]. The combination of a ketogenic diet with hyper-oxygen conditions also showed anti-tumor effects in mice [171]. However, chemotherapy frequently results in muscle wasting and cachexia, and thus patients undergoing chemotherapy are recommended to consume elevated calories and protein. In tumor bearing mice, high caloric food consumption increased survival, even in the absence of chemotherapy [173]. Still, dietary interventions in tandem with traditional therapeutics are under development and possible side effects, such as hypoglycemia, should be considered seriously [174]. Challenges & Strategies for targeting tumor metabolism

The major barrier to the development of these drugs is that many fail to specifically inhibit metabolic enzymes associated with cancer. Due to co-existence of multiple metabolic isoforms, many small molecule inhibitors for targeting metabolism can cause side effects since they may inhibit essential glycolytic and other metabolic pathways. Also, targeting a single metabolic step could lead to adaptive responses by another metabolic pathway, possibly resulting in side effects. Therefore, for the use of these strategies, we need to proactively investigate systematic effects of these drugs, including their toxicology and potential side effects in the kidneys or other organs.

Tumor microenvironment & immunometabolism

The influence of tumor microenvironment on glycolytic metabolism

Due to rapid growth and altered metabolism, the solid tumor contains areas of hypoxia (low oxygen), increased acidification (due to high rates of glycolysis) and energy substrate limitation (due to increased distance from supporting blood vessels). Tumor cells adapt and thrive in these seemingly hostile environments by activating multiple cell survival pathways. Hypoxia-inducible factors (HIFs) are master transcription factors required for metabolic and survival adaptations to hypoxia [175]. Active HIF1 is a heterodimer of an oxygen sensitive HIF-1α and constitutively expressed HIF-1β. HIF-1α stability in hypoxia allows for the transcription of many HIF-dependent genes, including multiple glycolytic genes [176, 177]. For example, HIF1α promotes the expression of pyruvate dehydrogenase kinase (PDK) 2 and PDK4 which inactivates PDH. PDH is responsible for converting pyruvate to acetyl-CoA, which is used in TCA cycle [139]. However, excessive PDK inactivates PDH and results in the suppression of TCA cycle and OXPHOS activities, shifting the generation of ATP toward glycolysis [178]. In non small cell lung cancer (NSCLC), aberrant expression of HIF1α stimulates HKII expression, contributing to elevated glycolysis [179]. In turn, PKM2 function as an upstream effector and binds to HIF1α, promoting glycolysis metabolism and tumorigenesis [180]. HIF-1α cooperates with c-Myc, an oncogenic transcription factor, and induces key metabolic genes, HK2 and PDK1 to promote glycolysis [137-139]. HIF-1α increases the expression of GLUT1, glucose uptake, and glucose phosphorylation [147, 181]. Reverse Warburg effect

The Warburg effect in the tumor microenvironment has recently been investigated from a different perspective, called reverse Warburg effect [182]. In this alternative model, epithelial cancer cells obtain energy from adjacent stromal fibroblasts, facilitating tumor growth [182]. These fibroblasts lose their stromal characteristics and are transformed into wound healing cells as a feeding source for cancer cells. In this transformed stroma, the absence of caveolin (marker for stroma) and high glycolytic enzyme expression is evident [182]. However, the specific conditions in which reverse Warburg effect occurs and how it affects tumorigenesis remain to be elucidated. IL-6 (Cytokine)/ CXCL14 effect on glycolysis and tumor microenvironment

In the tumor microenvironment, immunometabolism and cytokines cooperate and play critical roles in modulating the functions of immune cells and cancer cells [183, 184]. Cytokines are a family of secreted proteins that stimulate chemotaxis and cell growth. Specific proinflammatory cytokines are sometimes associated with cancer progression [185]. In OVCA patients, high level of the pro-inflammatory cytokine IL-6 is present in the serum and ascites, which is associated with poor clinical outcomes [185, 186]. Increased IL-6 and its receptor IL-6R induce invasion and metastasis of OVCA through activating the down-stream JAK-STAT3 pathway [187]. In a colon cancer mouse model, IL-6 treatment stimulated key glycolytic genes, including PFKFB3 and aerobic glycolysis, whereas the anti-IL-6R antibody decreased glycolysis [188], suggesting an important role of IL-6 in cellular metabolism.

Small cytokine, CXCL14 is a key driver for promoting metastasis of cancer-associated fibroblast (CAF) cells in breast and prostate cancer [189, 190]. CXCL14 is elevated in tumor stromal cells and promotes tumor cell proliferation and metastasis [189]. Clinically, an elevated level of CXCL14 is also correlated with poor prognosis [191]. In OVCA, CXCL14 in CAF mediates delivery of long non-coding RNA, LINC00092, a driver of metastasis [192]. Mechanistically, CAFs with high CXCL-14 promotes LINC00092 in OVCA. LINC0092 binds to PFKFB2, promoting cancer metastasis [192]. Chemokine growth-regulated oncogene (Gro)1 functions as an inducer of senescence in fibroblast, leading to malignant transformation of ovarian epithelial cells [193]. This suggests that Gro1 may be involved in the reverse Warburg effect, with adjacent fibroblasts providing nutrients to the cancer cells. Precisely how multiple cytokines interplay in the tumor microenvironment and regulate cellular metabolism remains to be determined.

Infiltrating T cells compete with tumor cells for energy substrates as both cell types consume copious energy. Incidentally, glucose deprivation of CD8(+) T cells in the tumor microenvironment decreases its cytotoxic action on tumor cells [12, 194]. Conversely, CD8(+) T cells abolish this effect by altering glutathione and cysteine metabolism in fibroblasts, suggesting a critical role of CD 8(+) T cells in chemosensitivity in tumor microenvironment [195]. Targeting glycolysis in cancer cells, but not T-cells, is therefore an important consideration when manipulating metabolism in the tumor microenvironment. Influence of exosome delivery on tumor metabolism

Exosomes are nano-sized vesicles derived from endocytic compartments and released by multiple cell types, including cancer cells. Accumulating evidence suggests that purified exosomes contain functional miRNA and small RNA, and LINK RNA [196]. Still, it remains unclear whether and how exosomes affect tumor microenvironment and tumor metabolism.

Nonetheless, using exosomes, cancer cell-derived miR-122 has been transferred to normal cells in premetastatic niches, thereby suppressing glucose uptake and utilization by down-regulating PK. Using glucose source derived from these niche cells, cancer cells facilitate the massive energy needs during metastatic growth [197]. This metabolic programming of cancer facilitates metastasis to other organs. Hence, cancer cell-derived extracellular miR-122 can reprogram systemic energy metabolism to facilitate disease progression and metastasis of breast cancer [197].

SUMMARY & FUTURE DIRECTIONS

Elevated metabolism is a key characteristic of multiple cancers. Many key glycolytic enzymes, including HKII, PFK, and PKM2 are elevated in tumor cells, and are involved in anti-apoptotic and cell survival mechanisms associated with chemoresistance. Considering that these enzymes are regulated by oncogenes (e.g., Akt, mTOR) and tumor suppressors (e.g., p53), it is likely that defective control of tumor suppressors may lead to dysregulated metabolism and growth of cancer cells. In addition, the tumor microenvironment contributes to elevated metabolism in cancer cells. In this context, targeting dysregulated metabolism may be an effective strategy to suppress tumor growth. However, recent clinical trials have demonstrated that targeting metabolism alone is not sufficient for cancer therapy. Instead, adjuvant chemotherapy in combination with targeting tumor metabolism may be the optimal therapeutic strategy, especially in overcoming chemoresistant ovarian cancer. With continued emphasis on the design of specific inhibitors of tumor metabolism, the application of combined therapies is likely to improve anti-cancer strategies.

ACKNOWLEDGMENTS

This work was supported by grants from the Canadian Institute of Health Research [CIHR; to BKT (MOP 126144) and to MEH (FDN143278)]. RBR, as an adjunct professor, is aided by the library facilities of McGill University. CYH is a recipient of doctoral admission scholarship from the University of Ottawa. DAP is a recipient of postdoctoral fellowship from Canadian Nuclear Laboratories.

CONFLICTS OF INTEREST

The authors declare no conflicts of interest exists.

• 1. Kurman RJ, Shih Ie M. Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications. Int J Gynecol Pathol. 2008; 27: 15160. doi: 10.1097/PGP.0b013e318161e4f5. [PubMed] https://doi.org/10.1097/PGP.0b013e318161e4f5.
• 2. Vang R, Shih Ie M, Kurman RJ. Ovarian low-grade and high-grade serous carcinoma: pathogenesis, clinicopathologic and molecular biologic features, and diagnostic problems. Adv Anat Pathol. 2009; 16: 267-82. doi: 10.1097/PAP.0b013e3181b4fffa. [PubMed] https://doi.org/10.1097/PAP.0b013e3181b4fffa.
• 3. Rosen DG, Yang G, Liu G, Mercado-Uribe I, Chang B, Xiao XS, Zheng J, Xue FX, Liu J. Ovarian cancer: pathology, biology, and disease models. Front Biosci (Landmark Ed). 2009; 14: 2089-102. [PubMed]
• 4. Hennessy BT, Coleman RL, Markman M. Ovarian cancer. Lancet. 2009; 374: 1371-82. doi: 10.1016/S01406736(09)61338-6. [PubMed] https://doi.org/10.1016/S01406736(0961338-6.
• 5. Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, Castedo M, Kroemer G. Molecular mechanisms of cisplatin resistance. Oncogene. 2012; 31: 1869-83. doi: 10.1038/onc.2011.384. [PubMed] https://doi.org/10.1038/onc.2011.384.
• 6. Fraser M, Bai T, Tsang BK. Akt promotes cisplatin resistance in human ovarian cancer cells through inhibition of p53 phosphorylation and nuclear function. Int J Cancer. 2008; 122: 534-46. doi: 10.1002/ijc.23086. [PubMed] https://doi.org/10.1002/ijc.23086.
• 7. Moll UM, Wolff S, Speidel D, Deppert W. Transcription-independent pro-apoptotic functions of p53. Curr Opin Cell Biol. 2005; 17: 631-6. doi: 10.1016/j.ceb.2005.09.007. [PubMed] https://doi.org/10.1016/j.ceb.2005.09.007.
• 8. Vousden KH, Lu X. Live or let die: the cell’s response to p53. Nat Rev Cancer. 2002; 2: 594-604. doi: 10.1038/nrc864. [PubMed] https://doi.org/10.1038/nrc864.
• 9. Richardson RB. p53 mutations associated with aging-related rise in cancer incidence rates. Cell Cycle. 2013; 12: 2468-78. doi: 10.4161/cc.25494. [PubMed] https://doi.org/10.4161/cc.25494.
• 10. Marabese M, Marchini S, Marrazzo E, Mariani P, Cattaneo D, Fossati R, Compagnoni A, Signorelli M, Moll UM, Codegoni AM, Broggini M. Expression levels of p53 and p73 isoforms in stage I and stage III ovarian cancer. Eur J Cancer. 2008; 44: 131-41. doi: 10.1016/j.ejca.2007.10.011. [PubMed] https://doi.org/10.1016/j.ejca.2007.10.011.
• 11. Hay N. Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy? Nat Rev Cancer. 2016; 16: 635-49. doi: 10.1038/nrc.2016.77. [PubMed] https://doi.org/10.1038/nrc.2016.77.
• 12. Warburg O. On the origin of cancer cells. Science. 1956; 123: 309-14. [PubMed]
• 13. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009; 324: 1029-33. doi: 10.1126/science.1160809. [PubMed] https://doi.org/10.1126/science.1160809.
• 14. Pfeiffer T, Morley A. An evolutionary perspective on the Crabtree effect. Front Mol Biosci. 2014; 1: 17. doi: 10.3389/fmolb.2014.00017. [PubMed] https://doi.org/10.3389/fmolb.2014.00017.
• 15. St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jager S, Handschin C, Zheng K, Lin J, Yang W, Simon DK, Bachoo R, Spiegelman BM. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell. 2006; 127: 397-408. doi: 10.1016/j.cell.2006.09.024. [PubMed] https://doi.org/10.1016/j.cell.2006.09.024.
• 16. Andrzejewski S, Klimcakova E, Johnson RM, Tabaries S, Annis MG, McGuirk S, Northey JJ, Chenard V, Sriram U, Papadopoli DJ, Siegel PM, St-Pierre J. PGC-1alpha Promotes Breast Cancer Metastasis and Confers Bioenergetic Flexibility against Metabolic Drugs. Cell Metab. 2017; 26: 778-87 e5. doi: 10.1016/j.cmet.2017.09.006. [PubMed] https://doi.org/10.1016/j.cmet.2017.09.006.
• 17. Pedersen PL. Warburg, me and Hexokinase 2: Multiple discoveries of key molecular events underlying one of cancers’ most common phenotypes, the “Warburg Effect”, i.e., elevated glycolysis in the presence of oxygen. J Bioenerg Biomembr. 2007; 39: 211-22. doi: 10.1007/s10863-007-9094-x. [PubMed] https://doi.org/10.1007/s10863-007-9094-x.
• 18. Zheng W, Feng Q, Liu J, Guo Y, Gao L, Li R, Xu M, Yan G, Yin Z, Zhang S, Liu S, Shan C. Inhibition of 6-phosphogluconate Dehydrogenase Reverses Cisplatin Resistance in Ovarian and Lung Cancer. Front Pharmacol. 2017; 8: 421. doi: 10.3389/fphar.2017.00421. [PubMed] https://doi.org/10.3389/fphar.2017.00421.
• 19. Catanzaro D, Gaude E, Orso G, Giordano C, Guzzo G, Rasola A, Ragazzi E, Caparrotta L, Frezza C, Montopoli M. Inhibition of glucose-6-phosphate dehydrogenase sensitizes cisplatin-resistant cells to death. Oncotarget. 2015; 6: 30102-14. doi: 10.18632/oncotarget.4945. [PubMed] https://doi.org/10.18632/oncotarget.4945.
• 20. Zhang C, Zhang D, Cheng JX. Coherent Raman Scattering Microscopy in Biology and Medicine. Annu Rev Biomed Eng. 2015; 17: 415-45. doi: 10.1146/annurevbioeng-071114-040554. [PubMed] https://doi.org/10.1146/annurev-bioeng-071114-040554.
• 21. Li J, Condello S, Thomes-Pepin J, Ma X, Xia Y, Hurley TD, Matei D, Cheng JX. Lipid Desaturation Is a Metabolic Marker and Therapeutic Target of Ovarian Cancer Stem Cells. Cell Stem Cell. 2017; 20: 303-14 e5. doi: 10.1016/j.stem.2016.11.004. [PubMed] https://doi.org/10.1016/j.stem.2016.11.004.
• 22. Iida Y, Aoki K, Asakura T, Ueda K, Yanaihara N, Takakura S, Yamada K, Okamoto A, Tanaka T, Ohkawa K. Hypoxia promotes glycogen synthesis and accumulation in human ovarian clear cell carcinoma. Int J Oncol. 2012; 40: 212230. doi: 10.3892/ijo.2012.1406. [PubMed] https://doi.org/10.1016/j.stem.2016.11.004.
• 23. Uekuri C, Shigetomi H, Ono S, Sasaki Y, Matsuura M, Kobayashi H. Toward an understanding of the pathophysiology of clear cell carcinoma of the ovary (Review). Oncol Lett. 2013; 6: 1163-73. doi: 10.3892/ol.2013.1550. [PubMed] https://doi.org/10.3892/ol.2013.1550.
• 24. Mathupala SP, Rempel A, Pedersen PL. Glucose catabolism in cancer cells: identification and characterization of a marked activation response of the type II hexokinase gene to hypoxic conditions. J Biol Chem. 2001; 276: 43407-12. doi: 10.1074/jbc.M108181200. [PubMed] https://doi.org/10.1074/jbc.M108181200.
• 25. Mathupala SP, Ko YH, Pedersen PL. Hexokinase II: cancer’s double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Oncogene. 2006; 25: 4777-86. doi: 10.1038/sj.onc.1209603. [PubMed] https://doi.org/10.1038/sj.onc.1209603.
• 26. Annibaldi A, Widmann C. Glucose metabolism in cancer cells. Curr Opin Clin Nutr Metab Care. 2010; 13: 466-70. doi: 10.1097/MCO.0b013e32833a5577. [PubMed] https://doi.org/10.1097/MCO.0b013e32833a5577.
• 27. Thorens B, Mueckler M. Glucose transporters in the 21st Century. Am J Physiol Endocrinol Metab. 2010; 298: E1415. doi: 10.1152/ajpendo.00712.2009. [PubMed] https://doi.org/10.1152/ajpendo.00712.2009.
• 28. Younes M, Brown RW, Stephenson M, Gondo M, Cagle PT. Overexpression of Glut1 and Glut3 in stage I nonsmall cell lung carcinoma is associated with poor survival. Cancer. 1997; 80: 1046-51. [PubMed]
• 29. Lidgren A, Bergh A, Grankvist K, Rasmuson T, Ljungberg B. Glucose transporter-1 expression in renal cell carcinoma and its correlation with hypoxia inducible factor-1 alpha. BJU Int. 2008; 101: 480-4. doi: 10.1111/j.1464410X.2007.07238.x. [PubMed] https://doi.org/10.1111/j.1464410X.2007.07238.x.
• 30. Pizzuti L, Sergi D, Mandoj C, Antoniani B, Sperati F, Chirico A, Di Lauro L, Valle M, Garofalo A, Vizza E, Corrado G, Tomao F, Rinaldi M, et al. GLUT 1 receptor expression and circulating levels of fasting glucose in high grade serous ovarian cancer. J Cell Physiol. 2018; 233: 1396-401. doi: 10.1002/jcp.26023. [PubMed] https://doi.org/10.1002/jcp.26023.
• 31. Gwak H, Haegeman G, Tsang BK, Song YS. Cancer-specific interruption of glucose metabolism by resveratrol is mediated through inhibition of Akt/GLUT1 axis in ovarian cancer cells. Mol Carcinog. 2014. doi: 10.1002/mc.22227. [PubMed] https://doi.org/10.1002/mc.22227.
• 32. Guo C, Ludvik AE, Arlotto ME, Hayes MG, Armstrong LL, Scholtens DM, Brown CD, Newgard CB, Becker TC, Layden BT, Lowe WL, Reddy TE. Coordinated regulatory variation associated with gestational hyperglycaemia regulates expression of the novel hexokinase HKDC1. Nat Commun. 2015; 6: 6069. doi: 10.1038/ncomms7069. [PubMed] https://doi.org/10.1038/ncomms7069.
• 33. Kabir F, Wilson JE. Mitochondrial hexokinase in brain: coexistence of forms differing in sensitivity to solubilization by glucose-6-phosphate on the same mitochondria. Arch Biochem Biophys. 1994; 310: 410-6. [PubMed]
• 34. Roberts DJ, Miyamoto S. Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy. Cell Death Differ. 2014. doi: 10.1038/cdd.2014.173. [PubMed] https://doi.org/10.1038/cdd.2014.208.
• 35. Majewski N, Nogueira V, Bhaskar P, Coy PE, Skeen JE, Gottlob K, Chandel NS, Thompson CB, Robey RB, Hay N. Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol Cell. 2004; 16: 819-30. doi: 10.1016/j.molcel.2004.11.014. [PubMed] https://doi.org/10.1016/j.molcel.2004.11.014.
• 36. Patra KC, Wang Q, Bhaskar PT, Miller L, Wang Z, Wheaton W, Chandel N, Laakso M, Muller WJ, Allen EL, Jha AK, Smolen GA, Clasquin MF, et al. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell. 2013; 24: 213-28. doi: 10.1016/j.ccr.2013.06.014. [PubMed] https://doi.org/10.1016/j.ccr.2013.06.014.
• 37. Wolf A, Agnihotri S, Micallef J, Mukherjee J, Sabha N, Cairns R, Hawkins C, Guha A. Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme. J Exp Med. 2011; 208: 313-26. doi: 10.1084/jem.20101470. [PubMed] https://doi.org/10.1084/jem.20101470.
• 38. Ha JH, Radhakrishnan R, Jayaraman M, Yan M, Ward JD, Fung KM, Moxley K, Sood AK, Isidoro C, Mukherjee P, Song YS, Dhanasekaran DN. LPA Induces Metabolic Reprogramming in Ovarian Cancer via a Pseudohypoxic Response. Cancer Res. 2018; 78: 1923-34. doi: 10.1158/0008-5472.CAN-17-1624. [PubMed] https://doi.org/10.1158/0008-5472.CAN-17-1624.
• 39. Zhang XY, Zhang M, Cong Q, Zhang MX, Zhang MY, Lu YY, Xu CJ. Hexokinase 2 confers resistance to cisplatin in ovarian cancer cells by enhancing cisplatin-induced autophagy. Int J Biochem Cell Biol. 2018; 95: 9-16. doi: 10.1016/j.biocel.2017.12.010. [PubMed] https://doi.org/10.1016/j.biocel.2017.12.010.
• 40. Yalcin A, Clem BF, Imbert-Fernandez Y, Ozcan SC, Peker S, O’Neal J, Klarer AC, Clem AL, Telang S, Chesney J. 6-Phosphofructo-2-kinase (PFKFB3) promotes cell cycle progression and suppresses apoptosis via Cdk1-mediated phosphorylation of p27. Cell Death Dis. 2014; 5: e1337. doi: 10.1038/cddis.2014.292. [PubMed] https://doi.org/10.1038/cddis.2014.292.
• 41. Costa Leite T, Da Silva D, Guimaraes Coelho R, Zancan P, Sola-Penna M. Lactate favours the dissociation of skeletal muscle 6-phosphofructo-1-kinase tetramers downregulating the enzyme and muscle glycolysis. Biochem J. 2007; 408: 123-30. doi: 10.1042/BJ20070687. [PubMed] https://doi.org/10.1042/BJ20070687.
• 42. Webb BA, Forouhar F, Szu FE, Seetharaman J, Tong L, Barber DL. Structures of human phosphofructokinase-1 and atomic basis of cancer-associated mutations. Nature. 2015; 523: 111-4. doi: 10.1038/nature14405. [PubMed] https://doi.org/10.1038/nature14405.
• 43. Atsumi T, Chesney J, Metz C, Leng L, Donnelly S, Makita Z, Mitchell R, Bucala R. High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers. Cancer Res. 2002; 62: 5881-7. [PubMed]
• 44. Taylor C, Mannion D, Miranda F, Karaminejadranjbar M, Herrero-Gonzalez S, Hellner K, Zheng Y, Bartholomeusz G, Bast RC, Jr., Ahmed AA. Loss of PFKFB4 induces cell death in mitotically arrested ovarian cancer cells. Oncotarget. 2017; 8: 17960-80. doi: 10.18632/oncotarget.14910. [PubMed] https://doi.org/10.18632/oncotarget.14910.
• 45. Israelsen WJ, Vander Heiden MG. Pyruvate kinase: Function, regulation and role in cancer. Semin Cell Dev Biol. 2015; 43: 43-51. doi: 10.1016/j.semcdb.2015.08.004. [PubMed] https://doi.org/10.1016/j.semcdb.2015.08.004.
• 46. Gao X, Wang H, Yang JJ, Liu X, Liu ZR. Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase. Mol Cell. 2012; 45: 598-609. doi: 10.1016/j.molcel.2012.01.001. [PubMed] https://doi.org/10.1016/j.molcel.2012.01.001.
• 47. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008; 452: 230-3. doi: 10.1038/nature06734. [PubMed] https://doi.org/10.1038/nature06734.
• 48. Chao TK, Huang TS, Liao YP, Huang RL, Su PH, Shen HY, Lai HC, Wang YC. Pyruvate kinase M2 is a poor prognostic marker of and a therapeutic target in ovarian cancer. PLoS One. 2017; 12: e0182166. doi: 10.1371/journal.pone.0182166. [PubMed] https://doi.org/10.1371/journal.pone.0182166.
• 49. Wang YH, Israelsen WJ, Lee D, Yu VWC, Jeanson NT, Clish CB, Cantley LC, Vander Heiden MG, Scadden DT. Cell-state-specific metabolic dependency in hematopoiesis and leukemogenesis. Cell. 2014; 158: 1309-23. doi: 10.1016/j.cell.2014.07.048. [PubMed] https://doi.org/10.1016/j.cell.2014.07.048.
• 50. Kobierzycki C, Piotrowska A, Latkowski K, Zabel M, Nowak-Markwitz E, Spaczynski M, Kedzia W, Pula B, Podhorska-Okolow M, Dziegiel P. Correlation of Pyruvate Kinase M2 Expression with Clinicopathological Data in Ovarian Cancer. Anticancer Res. 2018; 38: 295-300. doi: 10.21873/anticanres.12221. [PubMed]
• 51. Vousden KH, Ryan KM. p53 and metabolism. Nat Rev Cancer. 2009; 9: 691-700. doi: 10.1038/nrc2715. [PubMed] https://doi.org/10.1038/nrc2715.
• 52. Xie H, Valera VA, Merino MJ, Amato AM, Signoretti S, Linehan WM, Sukhatme VP, Seth P. LDH-A inhibition, a therapeutic strategy for treatment of hereditary leiomyomatosis and renal cell cancer. Mol Cancer Ther. 2009; 8: 626-35. doi: 10.1158/1535-7163.MCT-08-1049. [PubMed] https://doi.org/10.1158/1535-7163.MCT-08-1049.
• 53. Feron O. Pyruvate into lactate and back: from the Warburg effect to symbiotic energy fuel exchange in cancer cells. Radiother Oncol. 2009; 92: 329-33. doi: 10.1016/j.radonc.2009.06.025. [PubMed] https://doi.org/10.1016/j.radonc.2009.06.025.
• 54. Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer CJ, Kennedy KM, Diepart C, Jordan BF, Kelley MJ, Gallez B, Wahl ML, et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest. 2008; 118: 3930-42. doi: 10.1172/JCI36843. [PubMed] https://doi.org/10.1172/JCI36843.
• 55. Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004; 4: 891-9. doi: 10.1038/nrc1478. [PubMed] https://doi.org/10.1038/nrc1478.
• 56. Gatenby RA, Gawlinski ET, Gmitro AF, Kaylor B, Gillies RJ. Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res. 2006; 66: 5216-23. doi: 10.1158/00085472.CAN-05-4193. [PubMed] https://doi.org/10.1158/00085472.CAN-05-4193.
• 57. Schneider D, Halperin R, Langer R, Bukovsky I, Herman A. Peritoneal fluid lactate dehydrogenase in ovarian cancer. Gynecol Oncol. 1997; 66: 399-404. doi: 10.1006/gyno.1997.4792. [PubMed] https://doi.org/10.1006/gyno.1997.4792.
• 58. Boran N, Kayikcioglu F, Yalvac S, Tulunay G, Ekinci U, Kose MF. Significance of serum and peritoneal fluid lactate dehydrogenase levels in ovarian cancer. Gynecol Obstet Invest. 2000; 49: 272-4. doi: 10.1159/000010258. [PubMed] https://doi.org/10.1159/000010258.
• 59. San-Millan I, Brooks GA. Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg Effect. Carcinogenesis. 2017; 38: 119-33. doi: 10.1093/carcin/bgw127. [PubMed] https://doi.org/10.1093/carcin/bgw127.
• 60. Yan C, Yang F, Zhou C, Chen X, Han X, Liu X, Ma H, Zheng W. MCT1 promotes the cisplatin-resistance by antagonizing Fas in epithelial ovarian cancer. Int J Clin Exp Pathol. 2015; 8: 2710-8. [PubMed]
• 61. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144: 646-74. doi: 10.1016/j.cell.2011.02.013. [PubMed] https://doi.org/10.1016/j.cell.2011.02.013.
• 62. Vieira HL, Haouzi D, El Hamel C, Jacotot E, Belzacq AS, Brenner C, Kroemer G. Permeabilization of the mitochondrial inner membrane during apoptosis: impact of the adenine nucleotide translocator. Cell Death Differ. 2000; 7: 1146-54. doi: 10.1038/sj.cdd.4400778. [PubMed] https://doi.org/10.1038/sj.cdd.4400778.
• 63. Suh DH, Kim MA, Kim H, Kim MK, Kim HS, Chung HH, Kim YB, Song YS. Association of overexpression of hexokinase II with chemoresistance in epithelial ovarian cancer. Clin Exp Med. 2014; 14: 345-53. doi: 10.1007/s10238-013-0250-9. [PubMed] https://doi.org/10.1007/s10238-013-0250-9.
• 64. Bryson JM, Coy PE, Gottlob K, Hay N, Robey RB. Increased hexokinase activity, of either ectopic or endogenous origin, protects renal epithelial cells against acute oxidant-induced cell death. J Biol Chem. 2002; 277: 11392-400. doi: 10.1074/jbc.M110927200. [PubMed] https://doi.org/10.1074/jbc.M110927200.
• 65. Ahmad A, Ahmad S, Schneider BK, Allen CB, Chang LY, White CW. Elevated expression of hexokinase II protects human lung epithelial-like A549 cells against oxidative injury. Am J Physiol Lung Cell Mol Physiol. 2002; 283: L573-84. doi: 10.1152/ajplung.00410.2001. [PubMed] https://doi.org/10.1152/ajplung.00410.2001.
• 66. DeWaal D, Nogueira V, Terry AR, Patra KC, Jeon SM, Guzman G, Au J, Long CP, Antoniewicz MR, Hay N. Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat Commun. 2018; 9: 446. doi: 10.1038/s41467-017-02733-4. [PubMed] https://doi.org/10.1038/s41467-017-02733-4.
• 67. Vyssokikh MY, Brdiczka D. The function of complexes between the outer mitochondrial membrane pore (VDAC) and the adenine nucleotide translocase in regulation of energy metabolism and apoptosis. Acta Biochim Pol. 2003; 50: 389-404. doi: 035002389. [PubMed]
• 68. Sun L, Shukair S, Naik TJ, Moazed F, Ardehali H. Glucose phosphorylation and mitochondrial binding are required for the protective effects of hexokinases I and II. Mol Cell Biol. 2008; 28: 1007-17. doi: 10.1128/MCB.00224-07. [PubMed] https://doi.org/10.1128/MCB.00224-07.
• 69. Corona JC, Gimenez-Cassina A, Lim F, Diaz-Nido J. Hexokinase II gene transfer protects against neurodegeneration in the rotenone and MPTP mouse models of Parkinson’s disease. J Neurosci Res. 2010; 88: 1943-50. doi: 10.1002/jnr.22357. [PubMed] https://doi.org/10.1002/jnr.22357.
• 70. Gross A, McDonnell JM, Korsmeyer SJ. BCL-2 family members and the mitochondria in apoptosis. Genes Dev. 1999; 13: 1899-911. [PubMed]
• 71. Harris MH, Thompson CB. The role of the Bcl-2 family in the regulation of outer mitochondrial membrane permeability. Cell Death Differ. 2000; 7: 1182-91. doi: 10.1038/sj.cdd.4400781. [PubMed] https://doi.org/10.1038/sj.cdd.4400781.
• 72. Vander Heiden MG, Chandel NS, Li XX, Schumacker PT, Colombini M, Thompson CB. Outer mitochondrial membrane permeability can regulate coupled respiration and cell survival. Proc Natl Acad Sci U S A. 2000; 97: 4666-71. doi: 10.1073/pnas.090082297. [PubMed] https://doi.org/10.1073/pnas.090082297.
• 73. Gogvadze V, Orrenius S, Zhivotovsky B. Multiple pathways of cytochrome c release from mitochondria in apoptosis. Biochim Biophys Acta. 2006; 1757: 639-47. doi: 10.1016/j.bbabio.2006.03.016. [PubMed] https://doi.org/10.1016/j.bbabio.2006.03.016.
• 74. Pastorino JG, Shulga N, Hoek JB. Mitochondrial binding of hexokinase II inhibits Bax-induced cytochrome c release and apoptosis. J Biol Chem. 2002; 277: 7610-8. doi: 10.1074/jbc.M109950200. [PubMed] https://doi.org/10.1074/jbc.M109950200.
• 75. Majewski N, Nogueira V, Robey RB, Hay N. Akt inhibits apoptosis downstream of BID cleavage via a glucose-dependent mechanism involving mitochondrial hexokinases. Mol Cell Biol. 2004; 24: 730-40. [PubMed] https://doi.org/10.1128/MCB.24.2.730-740.2004.
• 76. Salani B, Marini C, Rio AD, Ravera S, Massollo M, Orengo AM, Amaro A, Passalacqua M, Maffioli S, Pfeffer U, Cordera R, Maggi D, Sambuceti G. Metformin impairs glucose consumption and survival in Calu-1 cells by direct inhibition of hexokinase-II. Sci Rep. 2013; 3: 2070. doi: 10.1038/srep02070. [PubMed] https://doi.org/10.1038/srep02070.
• 77. Zhou Y, Lu N, Qiao C, Ni T, Li Z, Yu B, Guo Q, Wei L. FV-429 induces apoptosis and inhibits glycolysis by inhibiting Akt-mediated phosphorylation of hexokinase II in MDAMB-231 cells. Mol Carcinog. 2016; 55: 1317-28. doi: 10.1002/mc.22374. [PubMed] https://doi.org/10.1002/mc.22374.
• 78. Chen Z, Zhang H, Lu W, Huang P. Role of mitochondria-associated hexokinase II in cancer cell death induced by 3-bromopyruvate. Biochim Biophys Acta. 2009; 1787: 55360. doi: 10.1016/j.bbabio.2009.03.003. [PubMed] https://doi.org/10.1016/j.bbabio.2009.03.003.
• 79. Neary CL, Pastorino JG. Akt inhibition promotes hexokinase 2 redistribution and glucose uptake in cancer cells. J Cell Physiol. 2013; 228: 1943-8. doi: 10.1002/jcp.24361. [PubMed] https://doi.org/10.1002/jcp.24361.
• 80. Krasnov GS, Dmitriev AA, Lakunina VA, Kirpiy AA, Kudryavtseva AV. Targeting VDAC-bound hexokinase II: a promising approach for concomitant anti-cancer therapy. Expert Opin Ther Targets. 2013; 17: 1221-33. doi: 10.1517/14728222.2013.833607. [PubMed] https://doi.org/10.1517/14728222.2013.833607.
• 81. Frezza C, Cipolat S, Martins de Brito O, Micaroni M, Beznoussenko GV, Rudka T, Bartoli D, Polishuck RS, Danial NN, De Strooper B, Scorrano L. OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell. 2006; 126: 177-89. doi: 10.1016/j.cell.2006.06.025. [PubMed] https://doi.org/10.1016/j.cell.2006.06.025.
• 82. Yamaguchi R, Lartigue L, Perkins G, Scott RT, Dixit A, Kushnareva Y, Kuwana T, Ellisman MH, Newmeyer DD. Opa1-mediated cristae opening is Bax/Bak and BH3 dependent, required for apoptosis, and independent of Bak oligomerization. Mol Cell. 2008; 31: 557-69. doi: 10.1016/j.molcel.2008.07.010. [PubMed] https://doi.org/10.1016/j.molcel.2008.07.010.
• 83. Kong B, Wang Q, Fung E, Xue K, Tsang BK. p53 Is Required for Cisplatin-induced Processing of the Mitochondrial Fusion Protein L-Opa1 That Is Mediated by the Mitochondrial Metallopeptidase Oma1 in Gynecologic Cancers. J Biol Chem. 2014; 289: 27134-45. doi: 10.1074/jbc.M114.594812. [PubMed] https://doi.org/10.1074/jbc.M114.594812.
• 84. Tsuyoshi H, Wong VKW, Han Y, Orisaka M, Yoshida Y, Tsang BK. Saikosaponin-d, a calcium mobilizing agent, sensitizes chemoresistant ovarian cancer cells to cisplatininduced apoptosis by facilitating mitochondrial fission and G2/M arrest. Oncotarget. 2017; 8: 99825-40. doi: 10.18632/oncotarget.21076. [PubMed] https://doi.org/10.18632/oncotarget.21076.
• 85. Mailloux RJ, Harper ME. Uncoupling proteins and the control of mitochondrial reactive oxygen species production. Free Radic Biol Med. 2011; 51: 1106-15. doi: 10.1016/j.freeradbiomed.2011.06.022. [PubMed] https://doi.org/10.1016/j.freeradbiomed.2011.06.022.
• 86. McMurray F, Patten DA, Harper ME. Reactive Oxygen Species and Oxidative Stress in Obesity-Recent Findings and Empirical Approaches. Obesity (Silver Spring). 2016; 24: 2301-10. doi: 10.1002/oby.21654. [PubMed] https://doi.org/10.1002/oby.21654.
• 87. Mailloux RJ, Dumouchel T, Aguer C, deKemp R, Beanlands R, Harper ME. Hexokinase II acts through UCP3 to suppress mitochondrial reactive oxygen species production and maintain aerobic respiration. Biochem J. 2011; 437: 301-11. doi: 10.1042/BJ20110571. [PubMed] https://doi.org/10.1042/BJ20110571.
• 88. Deng S, Yang Y, Han Y, Li X, Wang X, Li X, Zhang Z, Wang Y. UCP2 inhibits ROS-mediated apoptosis in A549 under hypoxic conditions. PLoS One. 2012; 7: e30714. doi: 10.1371/journal.pone.0030714. [PubMed] https://doi.org/10.1371/journal.pone.0030714.
• 89. Wallace DC. Mitochondria and cancer. Nat Rev Cancer. 2012; 12: 685-98. doi: 10.1038/nrc3365. [PubMed] https://doi.org/10.1038/nrc3365.
• 90. Grandemange S, Herzig S, Martinou JC. Mitochondrial dynamics and cancer. Semin Cancer Biol. 2009; 19: 50-6. doi: 10.1016/j.semcancer.2008.12.001. [PubMed] https://doi.org/10.1016/j.semcancer.2008.12.001.
• 91. Mishra P, Chan DC. Metabolic regulation of mitochondrial dynamics. J Cell Biol. 2016; 212: 379-87. doi: 10.1083/jcb.201511036. [PubMed] https://doi.org/10.1083/jcb.201511036.
• 92. Cogliati S, Frezza C, Soriano ME, Varanita T, Quintana-Cabrera R, Corrado M, Cipolat S, Costa V, Casarin A, Gomes LC, Perales-Clemente E, Salviati L, FernandezSilva P, et al. Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell. 2013; 155: 160-71. doi: 10.1016/j.cell.2013.08.032. [PubMed] https://doi.org/10.1016/j.cell.2013.08.032.
• 93. Patten DA, Wong J, Khacho M, Soubannier V, Mailloux RJ, Pilon-Larose K, MacLaurin JG, Park DS, McBride HM, Trinkle-Mulcahy L, Harper ME, Germain M, Slack RS. OPA1-dependent cristae modulation is essential for cellular adaptation to metabolic demand. EMBO J. 2014; 33: 267691. doi: 10.15252/embj.201488349. [PubMed] https://doi.org/10.15252/embj.201488349.
• 94. Farrand L, Kim JY, Im-Aram A, Suh JY, Lee HJ, Tsang BK. An improved quantitative approach for the assessment of mitochondrial fragmentation in chemoresistant ovarian cancer cells. PLoS One. 2013; 8: e74008. doi: 10.1371/journal.pone.0074008. [PubMed] https://doi.org/10.1371/journal.pone.0074008.
• 95. Farrand L, Byun S, Kim JY, Im-Aram A, Lee J, Lim S, Lee KW, Suh JY, Lee HJ, Tsang BK. Piceatannol enhances cisplatin sensitivity in ovarian cancer via modulation of p53, X-linked inhibitor of apoptosis protein (XIAP), and mitochondrial fission. J Biol Chem. 2013; 288: 23740-50. doi: 10.1074/jbc.M113.487686. [PubMed] https://doi.org/10.1074/jbc.M113.487686.
• 96. Li J, Huang Q, Long X, Guo X, Sun X, Jin X, Li Z, Ren T, Yuan P, Huang X, Zhang H, Xing J. Mitochondrial elongation-mediated glucose metabolism reprogramming is essential for tumour cell survival during energy stress. Oncogene. 2017; 36: 4901-12. doi: 10.1038/onc.2017.98. [PubMed] https://doi.org/10.1038/onc.2017.98.
• 97. Hagenbuchner J, Kiechl-Kohlendorfer U, Obexer P, Ausserlechner MJ. BIRC5/Survivin as a target for glycolysis inhibition in high-stage neuroblastoma. Oncogene. 2016; 35: 2052-61. doi: 10.1038/onc.2015.264. [PubMed] https://doi.org/10.1038/onc.2015.264.
• 98. Hagenbuchner J, Kuznetsov AV, Obexer P, Ausserlechner MJ. BIRC5/Survivin enhances aerobic glycolysis and drug resistance by altered regulation of the mitochondrial fusion/fission machinery. Oncogene. 2013; 32: 4748-57. doi: 10.1038/onc.2012.500. [PubMed] https://doi.org/10.1038/onc.2012.500.
• 99. Gomes LC, Di Benedetto G, Scorrano L. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol. 2011; 13: 589-98. doi: 10.1038/ncb2220. [PubMed] https://doi.org/10.1038/ncb2220.
• 100. Rambold AS, Kostelecky B, Elia N, Lippincott-Schwartz J. Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci U S A. 2011; 108: 10190-5. doi: 10.1073/pnas.1107402108. [PubMed] https://doi.org/10.1073/pnas.1107402108.
• 101. Palikaras K, Lionaki E, Tavernarakis N. Balancing mitochondrial biogenesis and mitophagy to maintain energy metabolism homeostasis. Cell Death Differ. 2015; 22: 1399401. doi: 10.1038/cdd.2015.86. [PubMed] https://doi.org/10.1038/cdd.2015.86.
• 102. Chaube B, Malvi P, Singh SV, Mohammad N, Viollet B, Bhat MK. AMPK maintains energy homeostasis and survival in cancer cells via regulating p38/PGC-1alphamediated mitochondrial biogenesis. Cell Death Discov. 2015; 1: 15063. doi: 10.1038/cddiscovery.2015.63. [PubMed] https://doi.org/10.1038/cddiscovery.2015.63.
• 103. Dominy JE, Puigserver P. Mitochondrial biogenesis through activation of nuclear signaling proteins. Cold Spring Harb Perspect Biol. 2013; 5. doi: 10.1101/cshperspect.a015008. [PubMed] https://doi.org/10.1101/cshperspect.a015008.
• 104. Wonsey DR, Zeller KI, Dang CV. The c-Myc target gene PRDX3 is required for mitochondrial homeostasis and neoplastic transformation. Proc Natl Acad Sci U S A. 2002; 99: 6649-54. doi: 10.1073/pnas.102523299. [PubMed] https://doi.org/10.1073/pnas.102523299.
• 105. Li F, Wang Y, Zeller KI, Potter JJ, Wonsey DR, O’Donnell KA, Kim JW, Yustein JT, Lee LA, Dang CV. Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol Cell Biol. 2005; 25: 6225-34. doi: 10.1128/MCB.25.14.6225-6234.2005. [PubMed] https://doi.org/10.1128/MCB.25.14.6225-6234.2005.
• 106. Wong CH, Iskandar KB, Yadav SK, Hirpara JL, Loh T, Pervaiz S. Simultaneous induction of non-canonical autophagy and apoptosis in cancer cells by ROS-dependent ERK and JNK activation. PLoS One. 2010; 5: e9996. doi: 10.1371/journal.pone.0009996. [PubMed] https://doi.org/10.1371/journal.pone.0009996.
• 107. Sabharwal SS, Schumacker PT. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat Rev Cancer. 2014; 14: 709-21. doi: 10.1038/nrc3803. [PubMed] https://doi.org/10.1038/nrc3803.
• 108. Motohashi H, Yamamoto M. Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol Med. 2004; 10: 549-57. doi: 10.1016/j.molmed.2004.09.003. [PubMed] https://doi.org/10.1016/j.molmed.2004.09.003.
• 109. Kim B, Jung JW, Jung J, Han Y, Suh DH, Kim HS, Dhanasekaran DN, Song YS. PGC1alpha induced by reactive oxygen species contributes to chemoresistance of ovarian cancer cells. Oncotarget. 2017; 8: 60299-311. doi: 10.18632/oncotarget.19140. [PubMed] https://doi.org/10.18632/oncotarget.19140.
• 110. Konstantinopoulos PA, Spentzos D, Fountzilas E, Francoeur N, Sanisetty S, Grammatikos AP, Hecht JL, Cannistra SA. Keap1 mutations and Nrf2 pathway activation in epithelial ovarian cancer. Cancer Res. 2011; 71: 5081-9. doi: 10.1158/0008-5472.CAN-10-4668. [PubMed] https://doi.org/10.1158/0008-5472.CAN-10-4668.
• 111. No JH, Kim YB, Song YS. Targeting nrf2 signaling to combat chemoresistance. J Cancer Prev. 2014; 19: 111-7. doi: 10.15430/JCP.2014.19.2.111. [PubMed] https://doi.org/10.15430/JCP.2014.19.2.111.
• 112. Godwin AK, Meister A, O’Dwyer PJ, Huang CS, Hamilton TC, Anderson ME. High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. Proc Natl Acad Sci U S A. 1992; 89: 3070-4. [PubMed] https://doi.org/10.1073/pnas.89.7.3070.
• 113. Fernandez-Checa JC, Kaplowitz N, Garcia-Ruiz C, Colell A, Miranda M, Mari M, Ardite E, Morales A. GSH transport in mitochondria: defense against TNF-induced oxidative stress and alcohol-induced defect. Am J Physiol. 1997; 273: G7-17. doi: 10.1152/ajpgi.1997.273.1.G7. [PubMed] https://doi.org/10.1152/ajpgi.1997.273.1.G7.
• 114. Armstrong JS, Steinauer KK, Hornung B, Irish JM, Lecane P, Birrell GW, Peehl DM, Knox SJ. Role of glutathione depletion and reactive oxygen species generation in apoptotic signaling in a human B lymphoma cell line. Cell Death Differ. 2002; 9: 252-63. doi: 10.1038/sj.cdd.4400959. [PubMed] https://doi.org/10.1038/sj.cdd.4400959.
• 115. Patra KC, Hay N. The pentose phosphate pathway and cancer. Trends Biochem Sci. 2014; 39: 347-54. doi: 10.1016/j.tibs.2014.06.005. [PubMed] https://doi.org/10.1016/j.tibs.2014.06.005.
• 116. Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell. 2005; 8: 179-83. doi: 10.1016/j.ccr.2005.08.008. [PubMed] https://doi.org/10.1016/j.ccr.2005.08.008.
• 117. Kotani K, Carozzi AJ, Sakaue H, Hara K, Robinson LJ, Clark SF, Yonezawa K, James DE, Kasuga M. Requirement for phosphoinositide 3-kinase in insulin-stimulated GLUT4 translocation in 3T3-L1 adipocytes. Biochem Biophys Res Commun. 1995; 209: 343-8. doi: 10.1006/bbrc.1995.1509. [PubMed] https://doi.org/10.1006/bbrc.1995.1509.
• 118. Shirai T, Tanaka K, Terada Y, Sawada T, Shirai R, Hashimoto Y, Nagata S, Iwamatsu A, Okawa K, Li S, Hattori S, Mano H, Fukui Y. Specific detection of phosphatidylinositol 3,4,5-trisphosphate binding proteins by the PIP3 analogue beads: an application for rapid purification of the PIP3 binding proteins. Biochim Biophys Acta. 1998; 1402: 292-302. [PubMed]
• 119. West KA, Castillo SS, Dennis PA. Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist Updat. 2002; 5: 234-48. [PubMed]
• 120. Scheid MP, Woodgett JR. PKB/AKT: functional insights from genetic models. Nat Rev Mol Cell Biol. 2001; 2: 7608. doi: 10.1038/35096067. [PubMed] https://doi.org/10.1038/35096067.
• 121. Vanhaesebroeck B, Alessi DR. The PI3K-PDK1 connection: more than just a road to PKB. Biochem J. 2000; 346 Pt 3: 561-76. [PubMed]
• 122. Miyamoto S, Murphy AN, Brown JH. Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II. Cell Death Differ. 2008; 15: 521-9. doi: 10.1038/sj.cdd.4402285. [PubMed] https://doi.org/10.1038/sj.cdd.4402285.
• 123. Roberts DJ, Tan-Sah VP, Smith JM, Miyamoto S. Akt phosphorylates HK-II at Thr-473 and increases mitochondrial HK-II association to protect cardiomyocytes. J Biol Chem. 2013; 288: 23798-806. doi: 10.1074/jbc.M113.482026. [PubMed] https://doi.org/10.1074/jbc.M113.482026.
• 124. Cheaib B, Auguste A, Leary A. The PI3K/Akt/mTOR pathway in ovarian cancer: therapeutic opportunities and challenges. Chin J Cancer. 2015; 34: 4-16. doi: 10.5732/cjc.014.10289. [PubMed] https://doi.org/10.5732/cjc.014.10289.
• 125. Hanrahan AJ, Schultz N, Westfal ML, Sakr RA, Giri DD, Scarperi S, Janakiraman M, Olvera N, Stevens EV, She QB, Aghajanian C, King TA, Stanchina E, et al. Genomic complexity and AKT dependence in serous ovarian cancer. Cancer Discov. 2012; 2: 56-67. doi: 10.1158/2159-8290.CD-11-0170. [PubMed] https://doi.org/10.1158/2159-8290.CD-11-0170.
• 126. Gasparri ML, Bardhi E, Ruscito I, Papadia A, Farooqi AA, Marchetti C, Bogani G, Ceccacci I, Mueller MD, Benedetti Panici P. PI3K/AKT/mTOR Pathway in Ovarian Cancer Treatment: Are We on the Right Track? Geburtshilfe Frauenheilkd. 2017; 77: 1095-103. doi: 10.1055/s-0043118907. [PubMed] https://doi.org/10.1055/s-0043-118907.
• 127. Gottlob K, Majewski N, Kennedy S, Kandel E, Robey RB, Hay N. Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev. 2001; 15: 1406-18. doi: 10.1101/gad.889901. [PubMed] https://doi.org/10.1101/gad.889901.
• 128. Ros S, Schulze A. Balancing glycolytic flux: the role of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases in cancer metabolism. Cancer Metab. 2013; 1: 8. doi: 10.1186/2049-3002-1-8. [PubMed] https://doi.org/10.1186/2049-3002-1-8.
• 129. Yun J, Rago C, Cheong I, Pagliarini R, Angenendt P, Rajagopalan H, Schmidt K, Willson JK, Markowitz S, Zhou S, Diaz LA, Jr., Velculescu VE, Lengauer C, et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science. 2009; 325: 1555-9. doi: 10.1126/science.1174229. [PubMed] https://doi.org/10.1126/science.1174229.
• 130. Barthel A, Okino ST, Liao J, Nakatani K, Li J, Whitlock JP, Jr., Roth RA. Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1. J Biol Chem. 1999; 274: 20281-6. [PubMed]
• 131. Foran PG, Fletcher LM, Oatey PB, Mohammed N, Dolly JO, Tavare JM. Protein kinase B stimulates the translocation of GLUT4 but not GLUT1 or transferrin receptors in 3T3-L1 adipocytes by a pathway involving SNAP-23, synaptobrevin-2, and/or cellubrevin. J Biol Chem. 1999; 274: 28087-95. [PubMed]
• 132. Eilers M, Eisenman RN. Myc’s broad reach. Genes Dev. 2008; 22: 2755-66. doi: 10.1101/gad.1712408. [PubMed] https://doi.org/10.1101/gad.1712408.
• 133. Ischenko I, Zhi J, Moll UM, Nemajerova A, Petrenko O. Direct reprogramming by oncogenic Ras and Myc. Proc Natl Acad Sci U S A. 2013; 110: 3937-42. doi: 10.1073/pnas.1219592110. [PubMed] https://doi.org/10.1073/pnas.1219592110.
• 134. Lawrenson K, Sproul D, Grun B, Notaridou M, Benjamin E, Jacobs IJ, Dafou D, Sims AH, Gayther SA. Modelling genetic and clinical heterogeneity in epithelial ovarian cancers. Carcinogenesis. 2011; 32: 1540-9. doi: 10.1093/carcin/bgr140. [PubMed] https://doi.org/10.1093/carcin/bgr140.
• 135. Reyes-Gonzalez JM, Armaiz-Pena GN, Mangala LS, Valiyeva F, Ivan C, Pradeep S, Echevarria-Vargas IM, Rivera-Reyes A, Sood AK, Vivas-Mejia PE. Targeting c-MYC in Platinum-Resistant Ovarian Cancer. Mol Cancer Ther. 2015; 14: 2260-9. doi: 10.1158/1535-7163.MCT-140801. [PubMed] https://doi.org/10.1158/1535-7163.MCT-14-0801.
• 136. Kim JW, Gao P, Liu YC, Semenza GL, Dang CV. Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol Cell Biol. 2007; 27: 7381-93. doi: 10.1128/MCB.00440-07. [PubMed] https://doi.org/10.1128/MCB.00440-07.
• 137. Kim JW, Dang CV. Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res. 2006; 66: 8927-30. doi: 10.1158/0008-5472.CAN-06-1501. [PubMed] https://doi.org/10.1158/0008-5472.CAN-06-1501.
• 138. Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006; 3: 177-85. doi: 10.1016/j.cmet.2006.02.002. [PubMed] https://doi.org/10.1016/j.cmet.2006.02.002.
• 139. Osthus RC, Shim H, Kim S, Li Q, Reddy R, Mukherjee M, Xu Y, Wonsey D, Lee LA, Dang CV. Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem. 2000; 275: 21797-800. doi: 10.1074/jbc.C000023200. [PubMed] https://doi.org/10.1074/jbc.C000023200.
• 140. Roberts DJ, Tan-Sah VP, Ding EY, Smith JM, Miyamoto S. Hexokinase-II positively regulates glucose starvationinduced autophagy through TORC1 inhibition. Mol Cell. 2014; 53: 521-33. doi: 10.1016/j.molcel.2013.12.019. [PubMed] https://doi.org/10.1016/j.molcel.2013.12.019.
• 141. Jiang S, Zhang HW, Lu MH, He XH, Li Y, Gu H, Liu MF, Wang ED. MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Cancer Res. 2010; 70: 3119-27. doi: 10.1158/0008-5472.CAN-09-4250. [PubMed] https://doi.org/10.1158/0008-5472.CAN-09-4250.
• 142. Yang X, Fraser M, Moll UM, Basak A, Tsang BK. Akt-mediated cisplatin resistance in ovarian cancer: modulation of p53 action on caspase-dependent mitochondrial death pathway. Cancer Res. 2006; 66: 3126-36. doi: 10.1158/0008-5472.CAN-05-0425. [PubMed] https://doi.org/10.1158/0008-5472.CAN-05-0425.
• 143. Berkers CR, Maddocks OD, Cheung EC, Mor I, Vousden KH. Metabolic regulation by p53 family members. Cell Metab. 2013; 18: 617-33. doi: 10.1016/j.cmet.2013.06.019. [PubMed] https://doi.org/10.1016/j.cmet.2013.06.019.
• 144. Wang L, Xiong H, Wu F, Zhang Y, Wang J, Zhao L, Guo X, Chang LJ, Zhang Y, You MJ, Koochekpour S, Saleem M, Huang H, et al. Hexokinase 2-mediated Warburg effect is required for PTEN- and p53-deficiency-driven prostate cancer growth. Cell Rep. 2014; 8: 1461-74. doi: 10.1016/j.celrep.2014.07.053. [PubMed] https://doi.org/10.1016/j.celrep.2014.07.053.
• 145. Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM. p53 regulates mitochondrial respiration. Science. 2006; 312: 1650-3. doi: 10.1126/science.1126863. [PubMed] https://doi.org/10.1126/science.1126863.
• 146. Assaily W, Benchimol S. Differential utilization of two ATP-generating pathways is regulated by p53. Cancer Cell. 2006; 10: 4-6. doi: 10.1016/j.ccr.2006.06.014. [PubMed] https://doi.org/10.1016/j.ccr.2006.06.014.
• 147. Cheung EC, Ludwig RL, Vousden KH. Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and lowers ROS and cell death. Proc Natl Acad Sci U S A. 2012; 109: 20491-6. doi: 10.1073/pnas.1206530109. [PubMed] https://doi.org/10.1073/pnas.1206530109.
• 148. Cheung EC, Vousden KH. The role of p53 in glucose metabolism. Curr Opin Cell Biol. 2010; 22: 186-91. doi: 10.1016/j.ceb.2009.12.006. [PubMed] https://doi.org/10.1016/j.ceb.2009.12.006.
• 149. Zhang C, Liu J, Liang Y, Wu R, Zhao Y, Hong X, Lin M, Yu H, Liu L, Levine AJ, Hu W, Feng Z. Tumour-associated mutant p53 drives the Warburg effect. Nat Commun. 2013; 4: 2935. doi: 10.1038/ncomms3935. [PubMed] https://doi.org/10.1038/ncomms3935.
• 150. Kosic M, Arsikin-Csordas K, Paunovic V, Firestone RA, Ristic B, Mircic A, Petricevic S, Bosnjak M, Zogovic N, Mandic M, Bumbasirevic V, Trajkovic V, Harhaji-Trajkovic L. Synergistic Anticancer Action of Lysosomal Membrane Permeabilization and Glycolysis Inhibition. J Biol Chem. 2016; 291: 22936-48. doi: 10.1074/jbc.M116.752113. [PubMed] https://doi.org/10.1074/jbc.M116.752113.
• 151. Liu H, Kurtoglu M, Leon-Annicchiarico CL, Munoz-Pinedo C, Barredo J, Leclerc G, Merchan J, Liu X, Lampidis TJ. Combining 2-deoxy-D-glucose with fenofibrate leads to tumor cell death mediated by simultaneous induction of energy and ER stress. Oncotarget. 2016; 7: 36461-73. doi: 10.18632/oncotarget.9263. [PubMed] https://doi.org/10.18632/oncotarget.9263.
• 152. Landau BR, Laszlo J, Stengle J, Burk D. Certain metabolic and pharmacologic effects in cancer patients given infusions of 2-deoxy-D-glucose. J Natl Cancer Inst. 1958; 21: 485-94. [PubMed]
• 153. Dwarakanath BS, Singh D, Banerji AK, Sarin R, Venkataramana NK, Jalali R, Vishwanath PN, Mohanti BK, Tripathi RP, Kalia VK, Jain V. Clinical studies for improving radiotherapy with 2-deoxy-D-glucose: present status and future prospects. J Cancer Res Ther. 2009; 5 Suppl 1: S21-6. doi: 10.4103/0973-1482.55136. [PubMed]
• 154. Goldin N, Arzoine L, Heyfets A, Israelson A, Zaslavsky Z, Bravman T, Bronner V, Notcovich A, Shoshan-Barmatz V, Flescher E. Methyl jasmonate binds to and detaches mitochondria-bound hexokinase. Oncogene. 2008; 27: 4636-43. doi: 10.1038/onc.2008.108. [PubMed] https://doi.org/10.1038/onc.2008.108.
• 155. Jae HJ, Chung JW, Park HS, Lee MJ, Lee KC, Kim HC, Yoon JH, Chung H, Park JH. The antitumor effect and hepatotoxicity of a hexokinase II inhibitor 3-bromopyruvate: in vivo investigation of intraarterial administration in a rabbit VX2 hepatoma model. Korean J Radiol. 2009; 10: 596-603. doi: 10.3348/kjr.2009.10.6.596. [PubMed] https://doi.org/10.3348/kjr.2009.10.6.596.
• 156. De Lena M, Lorusso V, Latorre A, Fanizza G, Gargano G, Caporusso L, Guida M, Catino A, Crucitta E, Sambiasi D, Mazzei A. Paclitaxel, cisplatin and lonidamine in advanced ovarian cancer. A phase II study. Eur J Cancer. 2001; 37: 364-8. [PubMed]
• 157. Clem BF, O’Neal J, Tapolsky G, Clem AL, Imbert-Fernandez Y, Kerr DA, 2nd, Klarer AC, Redman R, Miller DM, Trent JO, Telang S, Chesney J. Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer. Mol Cancer Ther. 2013; 12: 146170. doi: 10.1158/1535-7163.MCT-13-0097. [PubMed] https://doi.org/10.1158/1535-7163.MCT-13-0097.
• 158. Wong JY, Huggins GS, Debidda M, Munshi NC, De Vivo I. Dichloroacetate induces apoptosis in endometrial cancer cells. Gynecol Oncol. 2008; 109: 394-402. doi: 10.1016/j.ygyno.2008.01.038. [PubMed] https://doi.org/10.1016/j.ygyno.2008.01.038.
• 159. Galluzzi L, Kepp O, Vander Heiden MG, Kroemer G. Metabolic targets for cancer therapy. Nat Rev Drug Discov. 2013; 12: 829-46. doi: 10.1038/nrd4145. [PubMed] https://doi.org/10.1038/nrd4145.
• 160. Li B, Li X, Ni Z, Zhang Y, Zeng Y, Yan X, Huang Y, He J, Lyu X, Wu Y, Wang Y, Zheng Y, He F. Dichloroacetate and metformin synergistically suppress the growth of ovarian cancer cells. Oncotarget. 2016; 7: 59458-70. doi: 10.18632/oncotarget.10694. [PubMed] https://doi.org/10.18632/oncotarget.10694.
• 161. Kumar K, Wigfield S, Gee HE, Devlin CM, Singleton D, Li JL, Buffa F, Huffman M, Sinn AL, Silver J, Turley H, Leek R, Harris AL, et al. Dichloroacetate reverses the hypoxic adaptation to bevacizumab and enhances its antitumor effects in mouse xenografts. J Mol Med (Berl). 2013; 91: 749-58. doi: 10.1007/s00109-013-0996-2. [PubMed] https://doi.org/10.1007/s00109-013-0996-2.
• 162. Strum SB, Adalsteinsson O, Black RR, Segal D, Peress NL, Waldenfels J. Case report: Sodium dichloroacetate (DCA) inhibition of the “Warburg Effect” in a human cancer patient: complete response in non-Hodgkin’s lymphoma after disease progression with rituximab-CHOP. J Bioenerg Biomembr. 2013; 45: 307-15. doi: 10.1007/s10863-0129496-2. [PubMed] https://doi.org/10.1007/s10863-0129496-2.
• 163. Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D, Abdulkarim B, McMurtry MS, Petruk KC. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med. 2010; 2: 31ra4. doi: 10.1126/scitranslmed.3000677. [PubMed] https://doi.org/10.1126/scitranslmed.3000677.
• 164. Kasznicki J, Sliwinska A, Drzewoski J. Metformin in cancer prevention and therapy. Ann Transl Med. 2014; 2: 57. doi: 10.3978/j.issn.2305-5839.2014.06.01. [PubMed] https://doi.org/10.3978/j.issn.2305-5839.2014.06.01.
• 165. Marini C, Salani B, Massollo M, Amaro A, Esposito AI, Orengo AM, Capitanio S, Emionite L, Riondato M, Bottoni G, Massara C, Boccardo S, Fabbi M, et al. Direct inhibition of hexokinase activity by metformin at least partially impairs glucose metabolism and tumor growth in experimental breast cancer. Cell Cycle. 2013; 12: 3490-9. doi: 10.4161/cc.26461. [PubMed] https://doi.org/10.4161/cc.26461.
• 166. Gwak H, Kim Y, An H, Dhanasekaran DN, Song YS. Metformin induces degradation of cyclin D1 via AMPK/GSK3beta axis in ovarian cancer. Mol Carcinog. 2017; 56: 349-58. doi: 10.1002/mc.22498. [PubMed] https://doi.org/10.1002/mc.22498.
• 167. Chen L, Ahmad N, Liu X. Combining p53 stabilizers with metformin induces synergistic apoptosis through regulation of energy metabolism in castration-resistant prostate cancer. Cell Cycle. 2016; 15: 840-9. doi: 10.1080/15384101.2016.1151582. [PubMed] https://doi.org/10.1080/15384101.2016.1151582.
• 168. Griss T, Vincent EE, Egnatchik R, Chen J, Ma EH, Faubert B, Viollet B, DeBerardinis RJ, Jones RG. Metformin Antagonizes Cancer Cell Proliferation by Suppressing Mitochondrial-Dependent Biosynthesis. PLoS Biol. 2015; 13: e1002309. doi: 10.1371/journal.pbio.1002309. [PubMed] https://doi.org/10.1371/journal.pbio.1002309.
• 169. Health NIo. (2018). Clinical trial of metformin in ovarian cancer (8600 Rockville Pike, Bethesda, MD 20894 U.S. National Library of Medicine,). [PubMed]
• 170. Lee C, Raffaghello L, Brandhorst S, Safdie FM, Bianchi G, Martin-Montalvo A, Pistoia V, Wei M, Hwang S, Merlino A, Emionite L, de Cabo R, Longo VD. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci Transl Med. 2012; 4: 124ra27. doi: 10.1126/scitranslmed.3003293. [PubMed] https://doi.org/10.1126/scitranslmed.3003293.
• 171. Lee C, Longo VD. Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients. Oncogene. 2011; 30: 3305-16. doi: 10.1038/onc.2011.91. [PubMed] https://doi.org/10.1038/onc.2011.91.
• 172. Poff AM, Ari C, Seyfried TN, D’Agostino DP. The ketogenic diet and hyperbaric oxygen therapy prolong survival in mice with systemic metastatic cancer. PLoS One. 2013; 8: e65522. doi: 10.1371/journal.pone.0065522. [PubMed] https://doi.org/10.1371/journal.pone.0065522.
• 173. Niakan B. Spontaneous remission of cancer: steady and aggressive malignant growth faced with hypoxia or hypoglycemia. Med Hypotheses. 2010; 75: 505-6. doi: 10.1016/j.mehy.2010.07.006. [PubMed] https://doi.org/10.1016/j.mehy.2010.07.006.
• 174. Semenza GL. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest. 2013; 123: 3664-71. doi: 10.1172/JCI67230. [PubMed] https://doi.org/10.1172/JCI67230.
• 175. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995; 92: 5510-4. [PubMed] https://doi.org/10.1073/pnas.92.12.5510.
• 176. Ivan M, Haberberger T, Gervasi DC, Michelson KS, Gunzler V, Kondo K, Yang H, Sorokina I, Conaway RC, Conaway JW, Kaelin WG, Jr. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc Natl Acad Sci U S A. 2002; 99: 13459-64. doi: 10.1073/pnas.192342099. [PubMed] https://doi.org/10.1073/pnas.192342099.
• 177. Gogvadze V, Orrenius S, Zhivotovsky B. Mitochondria in cancer cells: what is so special about them? Trends Cell Biol. 2008; 18: 165-73. doi: 10.1016/j.tcb.2008.01.006. [PubMed] https://doi.org/10.1016/j.tcb.2008.01.006.
• 178. Ma Y, Yu C, Mohamed EM, Shao H, Wang L, Sundaresan G, Zweit J, Idowu M, Fang X. A causal link from ALK to hexokinase II overexpression and hyperactive glycolysis in EML4-ALK-positive lung cancer. Oncogene. 2016; 35: 6132-42. doi: 10.1038/onc.2016.150. [PubMed] https://doi.org/10.1038/onc.2016.150.
• 179. Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem. 1995; 270: 12307. [PubMed]
• 180. Chen C, Pore N, Behrooz A, Ismail-Beigi F, Maity A. Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia. J Biol Chem. 2001; 276: 9519-25. doi: 10.1074/jbc.M010144200. [PubMed] https://doi.org/10.1074/jbc.M010144200.
• 181. Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S, Pestell RG, MartinezOutschoorn UE, Sotgia F, et al. The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle. 2009; 8: 3984-4001. doi: 10.4161/cc.8.23.10238. [PubMed]
• 182. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013; 19: 1423-37. doi: 10.1038/nm.3394. [PubMed] https://doi.org/10.1038/nm.3394.
• 183. Bissell MJ, Hines WC. Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med. 2011; 17: 320-9. doi: 10.1038/nm.2328. [PubMed] https://doi.org/10.1038/nm.2328.
• 184. Lane D, Matte I, Rancourt C, Piche A. Prognostic significance of IL-6 and IL-8 ascites levels in ovarian cancer patients. BMC Cancer. 2011; 11: 210. doi: 10.1186/14712407-11-210. [PubMed] https://doi.org/10.1186/1471-2407-11-210.
• 185. Lane D, Matte I, Garde-Granger P, Laplante C, Carignan A, Rancourt C, Piche A. Inflammation-regulating factors in ascites as predictive biomarkers of drug resistance and progression-free survival in serous epithelial ovarian cancers. BMC Cancer. 2015; 15: 492. doi: 10.1186/s12885015-1511-7. [PubMed] https://doi.org/10.1186/s12885-015-1511-7.
• 186. Kumar J, Ward AC. Role of the interleukin 6 receptor family in epithelial ovarian cancer and its clinical implications. Biochim Biophys Acta. 2014; 1845: 117-25. doi: 10.1016/j.bbcan.2013.12.003. [PubMed] https://doi.org/10.1016/j.bbcan.2013.12.003.
• 187. Han J, Meng Q, Xi Q, Zhang Y, Zhuang Q, Han Y, Jiang Y, Ding Q, Wu G. Interleukin-6 stimulates aerobic glycolysis by regulating PFKFB3 at early stage of colorectal cancer. Int J Oncol. 2016; 48: 215-24. doi: 10.3892/ijo.2015.3225. [PubMed]
• 188. Augsten M, Hagglof C, Olsson E, Stolz C, Tsagozis P, Levchenko T, Frederick MJ, Borg A, Micke P, Egevad L, Ostman A. CXCL14 is an autocrine growth factor for fibroblasts and acts as a multi-modal stimulator of prostate tumor growth. Proc Natl Acad Sci U S A. 2009; 106: 34149. doi: 10.1073/pnas.0813144106. [PubMed] https://doi.org/10.1073/pnas.0813144106.
• 189. Augsten M, Sjoberg E, Frings O, Vorrink SU, Frijhoff J, Olsson E, Borg A, Ostman A. Cancer-associated fibroblasts expressing CXCL14 rely upon NOS1-derived nitric oxide signaling for their tumor-supporting properties. Cancer Res. 2014; 74: 2999-3010. doi: 10.1158/0008-5472.CAN-132740. [PubMed] https://doi.org/10.1158/0008-5472.CAN-132740.
• 190. Sjoberg E, Augsten M, Bergh J, Jirstrom K, Ostman A. Expression of the chemokine CXCL14 in the tumour stroma is an independent marker of survival in breast cancer. Br J Cancer. 2016; 114: 1117-24. doi: 10.1038/bjc.2016.104. [PubMed] https://doi.org/10.1038/bjc.2016.104.
• 191. Zhao L, Ji G, Le X, Wang C, Xu L, Feng M, Zhang Y, Yang H, Xuan Y, Yang Y, Lei L, Yang Q, Lau WB, et al. Long Noncoding RNA LINC00092 Acts in Cancer-Associated Fibroblasts to Drive Glycolysis and Progression of Ovarian Cancer. Cancer Res. 2017; 77: 1369-82. doi: 10.1158/00085472.CAN-16-1615. [PubMed] https://doi.org/10.1158/00085472.CAN-16-1615.
• 192. Yang G, Rosen DG, Zhang Z, Bast RC, Jr., Mills GB, Colacino JA, Mercado-Uribe I, Liu J. The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. Proc Natl Acad Sci U S A. 2006; 103: 16472-7. doi: 10.1073/pnas.0605752103. [PubMed] https://doi.org/10.1073/pnas.0605752103.
• 193. Zhao E, Maj T, Kryczek I, Li W, Wu K, Zhao L, Wei S, Crespo J, Wan S, Vatan L, Szeliga W, Shao I, Wang Y, et al. Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat Immunol. 2016; 17: 95-103. doi: 10.1038/ni.3313. [PubMed] https://doi.org/10.1038/ni.3313.
• 194. Wang W, Kryczek I, Dostal L, Lin H, Tan L, Zhao L, Lu F, Wei S, Maj T, Peng D, He G, Vatan L, Szeliga W, et al. Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer. Cell. 2016; 165: 1092105. doi: 10.1016/j.cell.2016.04.009. [PubMed] https://doi.org/10.1016/j.cell.2016.04.009.
• 195. Zucker S, Moll UM, Lysik RM, DiMassimo EI, Stetler-Stevenson WG, Liotta LA, Schwedes JW. Extraction of type-IV collagenase/gelatinase from plasma membranes of human cancer cells. Int J Cancer. 1990; 45: 1137-42. [PubMed]
• 196. Fong MY, Zhou W, Liu L, Alontaga AY, Chandra M, Ashby J, Chow A, O’Connor ST, Li S, Chin AR, Somlo G, Palomares M, Li Z, et al. Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat Cell Biol. 2015; 17: 183-94. doi: 10.1038/ncb3094. [PubMed] https://doi.org/10.1038/ncb3094.
• 197. Sun L, Yin Y, Clark LH, Sun W, Sullivan SA, Tran AQ, Han J, Zhang L, Guo H, Madugu E, Pan T, Jackson AL, Kilgore J, et al. Dual inhibition of glycolysis and glutaminolysis as a therapeutic strategy in the treatment of ovarian cancer. Oncotarget. 2017; 8: 63551-61. doi: 10.18632/oncotarget.18854. [PubMed] https://doi.org/10.18632/oncotarget.18854.
• 198. Shoshan MC. 3-Bromopyruvate: targets and outcomes. J Bioenerg Biomembr. 2012; 44: 7-15. doi: 10.1007/s10863012-9419-2. [PubMed] https://doi.org/10.1007/s10863012-9419-2.
• 199. Nath K, Nelson DS, Heitjan DF, Leeper DB, Zhou R, Glickson JD. Lonidamine induces intracellular tumor acidification and ATP depletion in breast, prostate and ovarian cancer xenografts and potentiates response to doxorubicin. NMR Biomed. 2015; 28: 281-90. doi: 10.1002/nbm.3240. [PubMed] https://doi.org/10.1002/nbm.3240.
• 200. Li J, Chen K, Wang F, Dai W, Li S, Feng J, Wu L, Liu T, Xu S, Xia Y, Lu J, Zhou Y, Xu L, et al. Methyl jasmonate leads to necrosis and apoptosis in hepatocellular carcinoma cells via inhibition of glycolysis and represses tumor growth in mice. Oncotarget. 2017; 8: 45965-80. doi: 10.18632/oncotarget.17469. [PubMed] https://doi.org/10.18632/oncotarget.17469.
• 201. Swiecicki PL, Bellile E, Sacco AG, Pearson AT, Taylor JM, Jackson TL, Chepeha DB, Spector ME, Shuman A, Malloy K, Moyer J, McKean E, McLean S, et al. A phase II trial of the BCL-2 homolog domain 3 mimetic AT-101 in combination with docetaxel for recurrent, locally advanced, or metastatic head and neck cancer. Invest New Drugs. 2016; 34: 481-9. doi: 10.1007/s10637-016-0364-5. [PubMed] https://doi.org/10.1007/s10637-016-0364-5.
• 202. Karaca B, Atmaca H, Bozkurt E, Kisim A, Uzunoglu S, Karabulut B, Sezgin C, Sanli UA, Uslu R. Combination of AT-101/cisplatin overcomes chemoresistance by inducing apoptosis and modulating epigenetics in human ovarian cancer cells. Mol Biol Rep. 2013; 40: 3925-33. doi: 10.1007/s11033-012-2469-z. [PubMed] https://doi.org/10.1007/s11033-012-2469-z.