Crosstalk between the Androgen Receptor and PPAR Gamma Signaling Pathways in the Prostate

Abstract

Nuclear receptors are a superfamily of ligand-activated transcription factors that play critical roles in the regulation of normal biological processes and several disease states. Of the nuclear receptors expressed within the prostate, the androgen receptor (AR) promotes the differentiation of prostatic epithelial cells and stimulates production of enzymes needed for liquefaction of semen. Multiple forms of AR also promote the growth of both early and late stage prostate cancers. As a result, drugs that target the AR signaling pathway are routinely used to treat patients with advanced forms of prostate cancer. Data also suggest that a second member of the nuclear receptor superfamily, the peroxisome proliferator activated receptor gamma (PPARγ), is a tumor suppressor that regulates growth of normal prostate and prostate cancers. Recent studies indicate there is a bidirectional interaction between AR and PPARγ, with each receptor influencing the expression and/or activity of the other within prostatic tissues. In this review, we examine how AR and PPARγ each regulate the growth and development of normal prostatic epithelial cells and prostate cancers. We also discuss interactions between the AR and PPARγ signaling pathways and how those interactions may influence prostate biology.

A hnRNP K–AR-Related Signature Reflects Progression toward Castration-Resistant Prostate Cancer

“…The TF XBP1, mediating cellular stress responses, is proposed as a predictor marker for PCa [ 34 ]. The bidirectional crosstalk between PPARG and AR regulates growth and development both in normal and in tumor prostate, as recently highlighted [ 35 ]. Using Cytoscape, we generated a network visualization of the predicted regulatory interaction between hK-TFs and 51 DIhKPs ( Figure S4 ).…”

“…Among the six hK-TFs, AR-controlled PPARG and HOX13 can be associated to ADT resistance. A recent study [ 35 ] has reported that PPARG controls prostate cell growth and differentiation and is involved in androgen-dependent PCa and CRPC evolution, acting as a tumor suppressor through its interplay with AR. The TF HOXA13, whose expression is associated with unfavorable survival [ 32 ], and the HOXB13, which controls PCa cell growth by inhibiting AR signaling [ 31 ], are also involved in PCa evolution.…”

Clinical Efficacy of a Novel Therapeutic Principle, Anakoinosis

“…Long-term responses at PSA levels <0.1 ng/ml occurred in rapidly progressive prostate cancer with PSA doubling times <3 months using combined transcriptional modulation, dexamethasone and pioglitazone in addition to metronomic low-dose chemotherapy. Pioglitazone may activate PPARγ, which is suggested to be a tumor suppressor in prostate cancer (Olokpa et al, 2017 ). The addition of imatinib in this schedule did not add any benefit.…”

The miR-96 and RARγ signaling axis governs androgen signaling and prostate cancer progression

“…In fact, multiple NRs are expressed in the normal prostate and are disrupted in PCa. NR actions are integrated by shared genomic binding regions, shared co-factors and the coregulation of ligand availability 61 . Non-coding RNAs including miRNA and lncRNA target NRs, their co-factors and target genes to also exert control of signaling 74,77 .…”