C-FABP-PPARγ-VEGF Signaling Axis Promotes TumorigenicityIn Castration Resistant Prostate Cancer

In previous work, it is suggested that the excessive amount of fatty acids transported by C-FABPmay have facilitated malignant progression of prostatic cancer cells through a C-FABP-PPARγ-VEGFaxis to increase angiogenesis and through another C-FABP-PPARγ route to inhibit apoptosis. Tofurther functionally characterised the C-FABP-PPARγ-VEGF axis, we have, in this work,investigated the molecular mechanisms involved in its tumoriegnicity promoting role in prostatecancer. Suppression of PPARγ in highly malignant prostate cancer cells produced a significantreduction in their proliferation rate (up to 53%), invasiveness (up to 89%) and anchorageindependentgrowth (up to 94%) in vitro. Knockdown of PPARγ gene in PC3-M cells significantlyreduced the average size of tumours formed in nude mice by 99%. Tumour incidence was reduced by90% and the latent period was significantly prolonged by 3.5 fold. The results in this study alsoshowed that C-FABP promoted VEGF expression and angiogenesis through PPARγ which wasactivated by the stimulation of the fatty acids transported by C-FABP. Further investigationsshowed that PPARγ up-regulated VEGF expression through acting with the PPAR-responsiveelements in the promoter region of VEGF gene in prostate cancer cells. Although androgen canmodulate VEGF expression through Sp1/Sp3 binding site on VEGF promoter in androgen-dependentprostate cancer cells, this route, disappeared as the cells gradually lost their androgendependency; was gradually replcaced by the C-FABP-PPARγ-VEGF axis. These results suggestedthat the C-FABP-PPARγ-VEGF axis, rather than androgen modulated route, may be a moreimportant novel therapeutic target for treatment of castration resistant prostatic cancer.