The Androgen Receptor Regulates PPARγ Expression and Activity in Human Prostate Cancer Cells

The peroxisome proliferator activated receptor gamma (PPAR gamma) is a ligand-activated transcription factor that regulates growth and differentiation within normal prostate and prostate cancers. However the factors that control PPAR gamma within the prostate cancers have not been characterized. The goal of this study was to examine whether the androgen receptor (AR) regulates PPAR gamma expression and function within human prostate cancer cells. qRT-PCR and Western blot analyses revealed nanomolar concentrations of the AR agonist dihydrotestosterone (DHT) decrease PPAR gamma mRNA and protein within the castration-resistant, AR-positive C4-2 and VCaP human prostate cancer cell lines. The AR antagonists bicalutamide and enzalutamide blocked the ability of DHT to reduce PPAR gamma levels. In addition, siRNA mediated knockdown of AR increased PPAR gamma protein levels and ligand-induced PPAR gamma transcriptional activity within the C4-2 cell line. Furthermore, proteasome inhibitors that interfere with AR function increased the level of basal PPAR gamma and prevented the DHT-mediated suppression of PPAR gamma. These data suggest that AR normally functions to suppress PPAR gamma expression within AR-positive prostate cancer cells. To determine whether increases in AR protein would influence PPAR gamma expression and activity, we used lipofectamine-based transfections to overexpress AR within the AR-null PC-3 cells. The addition of AR to PC-3 cells did not significantly alter PPAR gamma protein levels. However, the ability of the PPAR gamma ligand rosiglitazone to induce activation of a PPAR gamma-driven luciferase reporter and induce expression of FABP4 was suppressed in AR-positive PC-3 cells. Together, these data indicate AR serves as a key modulator of PPAR gamma expression and function within prostate tumors. (C) 2016 Wiley Periodicals, Inc.