Deciphering the Roles of Thiazolidinediones and PPAR γ in Bladder Cancer

Abstract

The use of thiazolidinedione (TZD) therapy in type II diabetic patients has proven useful in the lowering of blood glucose levels. However, recent investigations have shown that there may be potential health concerns associated, including the risk of developing bladder cancer as well as complications in the cardiovasculature. TZDs are ligands for the nuclear receptor PPARγ, and activation causes lipid uptake and insulin sensitization, both of which are critical processes for diabetic patients whose bodies are unable to utilize insulin effectively. Several studies have shown that PPARγ/TZDs decrease IGF-1 levels and, thus, reduce cancer growth in carcinomas such as the pancreas, colon, liver, and prostate. However, other studies have shed light on the potential of the receptor as a biomarker for uroepithelial carcinomas, particularly due to its stimulatory effect on migration of bladder cancer cells. Furthermore, PPARγ may provide the tumor-promoting microenvironment by de novo synthesis of nutrients that are needed for bladder cancer development. In this review, we closely examine the TZD class of drugs and their effects on PPARγ in patient studies along with additional molecular factors that are positive modulators, such as protein phosphatase 5 (PP5), which may have considerable implications for bladder cancer therapy.

Figure 1

PPARγ heterodimerizes with RXR for transcriptional regulation. PPARγ ligands such as eicosanoids (EETs), fatty acids, or thiazolidinediones (TZDs) bind to PPARγ to cause transactivation resulting in the binding to regulatory regions on DNA. PPARγ combines with retinoid X receptors (RXRs) to form heterodimers, which together serve as transcriptional activators for various genes by binding to specific PPAR response elements (PPREs) in their promoters.

Figure 2

Theoretical model of PPARγ and PP5 in bladder cancer. Activation of PPARγ by TZDs recruits PP5 to positively modulate and dephosphorylate Ser-112 (S112). PPARγ is activated once the phosphate group is removed, and a series of PPARγ-mediated activities commence shortly thereafter, including insulin sensitization. PP5 has been shown to mediate PPARγ activity by controlling phosphorylation of S112 in an adipogenic model, and targeting PP5 in the bladder epithelium may potentially affect PPARγ and its carcinogenic effects on the bladder.