Abstract
BackgroundAlthough PPARγ antagonists have shown considerable pre-clinical efficacy, recent studies suggest PPARγ ligands induce PPARγ-independent effects. There is a need to better define such effects to permit rational utilization of these agents.MethodsWe have studied the effects of a range of endogenous and synthetic PPARγ ligands on proliferation, growth arrest (FACS analysis) and apoptosis (caspase-3/7 activation and DNA fragmentation) in multiple prostate carcinoma cell lines (DU145, PC-3 and LNCaP) and in a series of cell lines modelling metastatic transitional cell carcinoma of the bladder (TSU-Pr1, TSU-Pr1-B1 and TSU-Pr1-B2).Results15-deoxy-prostaglandin J2 (15dPGJ2), troglitazone (TGZ) and to a lesser extent ciglitazone exhibited inhibitory effects on cell number; the selective PPARγ antagonist GW9662 did not reverse these effects. Rosiglitazone and pioglitazone had no effect on proliferation. In addition, TGZ induced G0/G1 growth arrest whilst 15dPGJ2 induced apoptosis.ConclusionTroglitazone and 15dPGJ2 inhibit growth of prostate and bladder carcinoma cell lines through different mechanisms and the effects of both agents are PPARγ-independent.
Highlights
PPARγ antagonists have shown considerable pre-clinical efficacy, recent studies suggest PPARγ ligands induce PPARγ-independent effects
Reports of PPARγ ligand induced growth inhibition demonstrate three important points: i) Growth inhibition can be specific to members of the thiazolidinedione family [18,19] ii) Growth inhibition can be selective for an endogenous PPARγ ligand compared to synthetic ligand [22], iii) PPARγ ligand mediated growth inhibition is PPARγ-independent in some cancer types [24,39]
Further to the PPARγ-independent effects of TGZ and 15-deoxy-prostaglandin J2 (15dPGJ2) discovered in prostate and bladder carcinoma, our study demonstrates that TGZ and 15dPGJ2 induce growth inhibition via different mechanisms
Summary
PPARγ antagonists have shown considerable pre-clinical efficacy, recent studies suggest PPARγ ligands induce PPARγ-independent effects. While previous studies demonstrate that some PPARγ ligands inhibit growth of multiple carcinoma cell lines [6,15,16,17], many reports demonstrate that PPARγ ligand-mediated growth inhibition can vary depending on the cancer type. Even within a carcinoma type, growth inhibition induced by PPARγ ligands can be cell line specific [23]. Studies utilising the irreversible PPARγ-selective antagonist GW9662, have revealed PPARγ-dependent and -independent mechanisms of growth inhibition [21,24,25,26], further highlighting the incongruity of responsiveness between cancer types
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