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Peroxisome proliferator‐activated receptor gamma controls prostate cancer cell growth through AR‐dependent and independent mechanisms
Author(s) -
Elix Catherine C.,
Salgia Meghan M.,
OttoDuessel Maya,
Copeland Ben T.,
Yoo Christopher,
Lee Michael,
Tew Ben Yi,
Ann David,
Pal Sumanta K.,
Jones Jeremy O.
Publication year - 2020
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.23928
Subject(s) - peroxisome proliferator activated receptor , nuclear receptor , androgen receptor , cancer research , receptor , prostate cancer , biology , cell growth , small interfering rna , apoptosis , downregulation and upregulation , endocrinology , medicine , cancer , cell culture , transcription factor , transfection , biochemistry , genetics , gene
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 (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. Methods Immunohistochemistry 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. Results We 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. Conclusions Having 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.