Inactivated FABP5 suppresses malignant progression of prostate cancer cells by inhibiting the activation of nuclear fatty acid receptor PPARγ
Waseem Al-Jameel1,5, Xiaojun Gou2, Xi Jin3, Jiacheng Zhang1, Qiang Wei3, Jianzhong Ai3, Hong Li3, Asmaa Al-Bayati1, Angela Platt-Higgins4, Andrew Pettitt1, Philip S. Rudland4 and Youqiang Ke1
1 Department of Molecular and Clinical Cancer Medicine, Liverpool University, Liverpool, United Kingdom
2 Sichuan Antibiotics Industrial Institute, Chengdu University, Chengdu, China
3 Institute of Urological Research, West China Hospital, Sichuan University, Chengdu, China
4 Department of Biochemistry, Liverpool University, Liverpool, United Kingdom
5 Department of Pathology, College of Veterinary Medicine, University of Mosul, Mosul, Iraq
Correspondence:
Youqiang Ke, email:
Keywords: FABP5; dmrFABP5; PPARγ; CRPC; tumorigenicity
Received: January 08, 2019 Accepted: May 20, 2019 Published: May 24, 2019
Abstract
Previous study has suggested that the FABP5-PPARγ-signalling transduction pathway gradually replaces the androgen receptor activated pathway in promoting malignant progression of castration-resistant prostate cancer (CRPC) cells. To interfere with this newly discovered FABP5-related signalling pathway, we have produced a highly efficient recombinant FABP5 inhibitor, named dmrFABP5. Treatment with dmrFABP5 significantly supressed the proliferation, migration, invasion and colony formation of the highly malignant prostate cancer cells PC3-M in vitro. To test dmrFABP5’s suppressive effect in CRPC, the human PC3-M cells were implanted orthotopically into the prostate gland of immunosuppressed mice to produce tumours. These mice were then treated with dmrFABP5 and produced a highly significant reduction of 100% in metastatic rate and a highly significant reduction of 13-fold in the average size of primary tumours. Immunocytochemial staining showed that the staining intensity of dmrFABP5 treated tumours was reduced by 67%. When tested in vitro, dmrFABP5 suppressed the cancer cells by blocking fatty acid stimulation of PPARγ, and thereby prevented it activating down-stream cancer-promoting or inhibiting cancer-suppressing genes. Our results show that the FABP5 inhibitor dmrFABP5 is a novel molecule for treatment of experimental CRPC and its inhibitory effect is much greater than that produced by SB-FI-26 reported in our previous work.
