The role of PPARγ in prostate cancer development and progression

Abstract

Advanced and metastatic prostate cancer is often incurable, but its dependency on certain molecular alterations may provide the basis for targeted therapies. A growing body of research has demonstrated that peroxisome proliferator-activated receptor gamma (PPARγ) is amplified as prostate cancer progresses. PPARγ has been shown to support prostate cancer growth through its roles in fatty acid synthesis, mitochondrial biogenesis, and co-operating with androgen receptor signalling. Interestingly, splice variants of PPARγ may have differing and contrasting roles. PPARγ itself is a highly druggable target, with agonists having been used for the past two decades in treating diabetes. However, side effects associated with these compounds have currently limited clinical use of these drugs in prostate cancer. Further understanding of PPARγ and novel techniques to target it, may provide therapies for advanced prostate cancer.

Fig. 1. Comparison of PPARγ splice variants.

Various PPARγ splice variants can be produced by alternative splicing events including exon skipping and readthrough. These variants each have unique structures and tissues specificity. The most well studied variants PPARγ1 and PPARγ1 however are of the most interest in prostate cancer currently.

Fig. 2. PPARγ signalling that positively regulate prostate cancer growth.

PPARγ peroxisome proliferator-activated receptor gamma, FASN fatty acid synthase, ACYL ATP citrate lyase, AR androgen receptor, AKT3 AKT serine/threonine kinase 3, CRM1 chromosome region maintenance 1, PCG1α PPARG coactivator 1 alpha.

Fig. 3. PPARγ alterations in PC (CBioPortal).

PPARγ alterations visualised using CBioPortal [42, 43]. Prostate adenocarcinoma TCGA (51) was used as the primary prostate cancer cohort [40]. Metastatic prostate adenocarcinoma (SU2C/PCF) was used as the metastatic prostate cancer cohort [41]. For mRNA dysregulation, a z-score of >1.2 was used as a threshold relative to all samples.