PPAR gamma agonists attenuate proliferation and modulate Wnt/â-catenin signalling in melanoma cells

Peroxisome proliferator-activated receptor-gamma (PPARã) is a member of the nuclear hormone receptor (NHR) superfamily of ligand-activated transcriptional regulators. Accumulating evidence suggests that PPARã 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 PPARã modulators in human melanoma cell lines. Ablation of PPARã 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 PPARã. The mechanisms underlying the anti-proliferative effects of PPARã in melanoma cells involve the regulation of expression of a number of critical cell cycle genes and â-catenin. Moreover, our data indicate that PPARã modulates Wnt/â-catenin mediated signalling in melanoma cells in an agonist dependent manner.