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

Abstract

BackgroundProstate 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 (PPARγ), a nuclear receptor that regulates fatty acid (FA) metabolism, as a novel target in PC, and suggest that inhibitors of PPARγ could be used to treat existing disease. We hypothesized that PPARγ acts through AR‐dependent and independent mechanisms to control PC development and growth and that PPARγ inhibition is a viable PC treatment strategy.MethodsImmunohistochemistry was used to determine expression of PPARү in a cohort of patients with PC. Standard molecular techniques were used to investigate the PPARү signaling in PC cells as well a xenograft mouse model to test PPARү inhibition in vivo. Kaplan‐Meier curves were created using cBioportal.ResultsWe confirmed the expression of PPARү in human PC. We then showed that small molecule inhibition of PPARγ decreases the growth of AR‐positive and ‐negative PC cells in vitro and that T0070907, a potent PPARγ antagonist, significantly decreased the growth of human PC xenografts in nude mice. We found that PPARγ 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 PPARγ antagonists. Patients with increased PPARү target gene expression, but not alterations in PPARү itself, were found to have significantly worse overall survival.ConclusionsHaving elucidated the direct cancer cell effects of PPARγ inhibition, our studies have helped to determine the role of PPARγ in PC growth, and support the hypothesis that PPARγ inhibition is an effective strategy for PC treatment.

Lipogenesis inhibitors: therapeutic opportunities and challenges

“…Studies have been conducted with more-specific inhibitors that strengthen FAS as an anticancer target. Fasnall was shown to inhibit breast cancer 245 and prostate cancer cell growth 262 , and GSK2194069 inhibits the proliferation of non-small-cell lung cancer cell lines 248 . IPI-9119 (reF.…”

The role of PPARγ in prostate cancer development and progression

“…Small molecular inhibitors however may have even fewer side effects. Use of one small molecule, T0070907, was shown to impair growth of PC cell lines LCP and PC3 in vitro [70]. LCP cells were also used in a xenograft and treated with T0070907 whereupon 4/7 tumours could no longer be detected indicating a complete regression.…”

PPAR-γ Modulators as Current and Potential Cancer Treatments

“…Interestingly, regarding factors involved in cell cycle, another study has found that the pro-apoptotic genes c-Myc and Bax are inhibited while cell-cycle regulators PCNA, cyclin D1 and COX-2 are promoted along with PPAR-g activation (40,55). In several studies, with the cell culture of human renal cell carcinoma, human prostate cancer xenografts in nude mice, as well as brain cancer in vivo, the increased expression of PPAR-g are all prognostically negative and pro-metastatic (56)(57)(58).…”