Fatty acid activated PPARγ promotes tumorigenicity of prostate cancer cells by up regulating <i>VEGF</i> via PPAR responsive elements of the promoter

Abstract

// Farzad S. Forootan 1 , Shiva S. Forootan 1 , Xiaojun Gou 2 , Jin Yang 3 , Bichong Liu 4 , Danqing Chen 1 , Majed Saad Al Fayi 1 , Waseem Al-Jameel 1 , Philip S. Rudland 5 , Syed A. Hussain 1 , Youqiang Ke 1 1 Molecular Pathology Laboratory, Department of Molecular and Clinical Cancer Medicine, Liverpool University, Liverpool L69 3GA, United Kingdom 2 Antibiotics Research and Re-evaluation Key Laboratory, Sichuan Antibiotics Industrial Institute, Chengdu University, Chengdu 610081, China 3 Urology Department of Affiliated Hospital, Chengdu University, Chengdu 610081, China 4 Department of Pharmacology, School of Pharmacology and Bioengineering, Chengdu University, Chengdu 610081, China 5 Department of Biochemistry, Liverpool University, Liverpool L69 3GA, United Kingdom Correspondence to: Youqiang Ke, e-mail: yqk@liverpool.ac.uk Keywords: prostate cancer, FABP5, PPAR&gamma;, PPRE, VEGF Received: August 03, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: January 17, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: January 22, 2016 ABSTRACT In previous work, it is suggested that the excessive amount of fatty acids transported by FABP5 may facilitate the malignant progression of prostate cancer cells through a FABP5-PPAR&gamma;-VEGF signal transduction axis to increase angiogenesis. To further functionally characterise the FABP5-PPAR&gamma;-VEGF signal transduction pathway, we have, in this work, investigated the molecular mechanisms involved in its tumorigenicity promoting role in prostate cancer. Suppression of PPAR&gamma; in highly malignant prostate cancer cells produced a significant reduction (up to 53%) in their proliferation rate, invasiveness (up to 89%) and anchorage-independent growth (up to 94%) in vitro . Knockdown of PPAR&gamma; gene in PC3-M cells by siRNA significantly reduced the average size of tumours formed in nude mice by 99% and tumour incidence by 90%, and significantly prolonged the latent period by 3.5 fold. Results in this study combined with some previous results suggested that FABP5 promoted VEGF expression and angiogenesis through PPAR&gamma; which was activated by fatty acids transported by FABP5. Further investigations showed that PPAR&gamma; up-regulated VEGF expression through acting with the PPAR-responsive elements in the promoter region of VEGF gene in prostate cancer cells. Although androgen can modulate VEGF expression through Sp1/Sp3 binding site on VEGF promoter in androgen-dependent prostate cancer cells, this route, disappeared as the cells gradually lost their androgen dependency; was replaced by the FABP5-PPAR&gamma;-VEGF signalling pathway. These results suggested that the FABP5-PPAR&gamma;-VEGF signal transduction axis, rather than androgen modulated route, may be a more important novel therapeutic target for angiogenesis-suppression treatment of castration resistant prostate cancer.