PPARγ agonists attenuate proliferation and modulate Wnt/β-catenin signalling in melanoma cells

Peroxisome proliferator-activated receptor-gamma (PPARγ) is a member of the nuclear hormone receptor (NHR) superfamily of ligand-activated transcriptional regulators. Accumulating evidence suggests that PPARγ agonists such as the thiazolidinediones (TZDs) may prove to be useful anti-cancer agents exhibiting anti-proliferative and/or pro-apoptotic affects in a range of cancer cell types including melanoma, however, the mechanisms underlying this effect remain unclear. We have demonstrated the anti-proliferative effects of full and partial PPARγ modulators in human melanoma cell lines. Ablation of PPARγ expression in the MM96L melanoma cell line by siRNA mediated mechanisms attenuates the anti-proliferative effect of these agents suggesting this effect is directly mediated by PPARγ. The mechanisms underlying the anti-proliferative effects of PPARγ in melanoma cells involve the regulation of expression of a number of critical cell cycle genes and β-catenin. Moreover, our data indicate that PPARγ modulates Wnt/β-catenin mediated signalling in melanoma cells in an agonist dependent manner. Abbreviations: MITF, micropthalmia-related transcription factor; Q-RT-PCR, quantitative real-time PC