The peroxisome proliferator activated receptor gamma (PPARγ) is a ligand-activated transcription factor that regulates in vitro and in vivo growth of castration-resistant human prostate cancer (PCa) cells. However, the factors that control expression of PPARγ within human PCa have not been characterized. We have previously shown that the androgen dihydrotestosterone decreases PPARγ levels and transcriptional activity in human PCa cells. Dihydrotestosterone serves as a high affinity ligand for the 110 kD form of the androgen receptor (AR-FL). Recent studies have shown the development of castration-resistant forms of prostate cancer is not only due to reactivation of AR-FL but also results from the expression of androgen receptor splice variants (ARVs) that lack the ligand-binding domain of the receptor. The goal of this study is to define the extent to which AR-FL and an ARV found in castration-resistant prostate cancer, AR-V7, regulate PPARγ expression and function. We first examined the role of AR-FL in the AR-positive C4-2 cell line. siRNA-mediated knockdown of endogenous AR-FL within C4-2 cells increased PPARγ protein and transcriptional activity. We next used reporter assays to further define the role of AR-FL and AR-V7 in PPARγ function. In these experiments, we first transfected plasmid vectors that express the AR-V7 or AR-FL into the AR null PC-3 prostate cancer cell line. A luciferase-based reporter assay was then used to measure alterations in PPARγ transcriptional activity within transfected cells. The addition of AR-FL to PC-3 cells resulted in reduced basal PPARγ luciferase activity. The ability of the ligand rosiglitazone to increase PPARγ activation was also suppressed in AR-FL positive PC-3 cells. A comparable decrease in ligand-induced PPARγ activation was detected in PC-3 cells that expressed AR-V7. The reduction in PPARγ activity produced by AR-FL and AR-V7 was likely not due to alterations in PPAR gamma expression, for we did not detect a consistent reduction in PPARγ mRNA and protein in transfected cells. Overall these data suggest that both AR-FL and AR-V7 are negative regulators of PPARγ function. Moreover, the AR-V7 stimulated reduction in PPARγ activity does not require the presence of AR-FL. Studies currently are underway to define the effect of endogenous AR-V7 on PPARγ expression and activity. This project was supported by NIGMS RISE grant (2R25GM059994-13), a NCI Mentored Career Development Award (K01CA114253), and the Vanderbilt CTSA grant UL1 RR024975-01 from NCRR/NIH.

Citation Format: Emuejevoke Olokpa, Lamonica V. Stewart. PPARγ function is attenuated by full length androgen receptor and the AR-V7 variant in human prostate cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1848. doi:10.1158/1538-7445.AM2015-1848