Peroxisome proliferator-activated receptor gamma controls prostate cancer cell growth through AR-dependent and independent mechanisms

Background Prostate cancer (PC) remains a leading cause of cancer mortality and the most successful chemopreventative and treatment strategies for PC come from targeting the androgen receptor (AR). Although AR plays a key role, it is likely that other molecular pathways also contribute to PC, making it essential to identify and develop drugs against novel targets. Recent studies have identified peroxisome proliferator-activated receptor gamma (PPAR gamma), a nuclear receptor that regulates fatty acid (FA) metabolism, as a novel target in PC, and suggest that inhibitors of PPAR gamma could be used to treat existing disease. We hypothesized that PPAR gamma acts through AR-dependent and independent mechanisms to control PC development and growth and that PPAR gamma inhibition is a viable PC treatment strategy. Methods Immunohistochemistry was used to determine expression of PPAR & x4af; in a cohort of patients with PC. Standard molecular techniques were used to investigate the PPAR & x4af; signaling in PC cells as well a xenograft mouse model to test PPAR & x4af; inhibition in vivo. Kaplan-Meier curves were created using cBioportal. Results We confirmed the expression of PPAR & x4af; in human PC. We then showed that small molecule inhibition of PPAR gamma decreases the growth of AR-positive and -negative PC cells in vitro and that T0070907, a potent PPAR gamma antagonist, significantly decreased the growth of human PC xenografts in nude mice. We found that PPAR gamma antagonists or small interfering RNA (siRNA) do not affect mitochondrial activity nor do they cause apoptosis; instead, they arrest the cell cycle. In AR-positive PC cells, antagonists and siRNAs reduce AR transcript and protein levels, which could contribute to growth inhibition. AR-independent effects on growth appear to be mediated by effects on FA metabolism as the specific FASN inhibitor, Fasnall, inhibited PC cell growth but did not have an additive effect when combined with PPAR gamma antagonists. Patients with increased PPAR & x4af; target gene expression, but not alterations in PPAR & x4af; itself, were found to have significantly worse overall survival. Conclusions Having elucidated the direct cancer cell effects of PPAR gamma inhibition, our studies have helped to determine the role of PPAR gamma in PC growth, and support the hypothesis that PPAR gamma inhibition is an effective strategy for PC treatment.