Tumor metabolism regulating chemosensitivity in ovarian cancer
Chae Young Han1, David A. Patten3,4, Richard B. Richardson3, Mary-Ellen Harper4, and Benjamin K. Tsang1,2
1 Department of Obstetrics and Gynecology and Cellular and Molecular Medicine, University of Ottawa, and Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
2 State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao, China
3 Canadian Nuclear Laboratories (CNL), Radiobiology and Health Branch, Chalk River Laboratories, Chalk River, ON, Canada
4 Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada
Correspondence:
Benjamin K. Tsang, email:
Keywords: Ovarian Cancer, Chemoresistance, Tumor metabolism, hexokinase 2, p53
Received: June 12, 2018 Accepted: August 14, 2018 Published: August 25, 2018
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.
