Growth Inhibition and Differentiation Induced by Peroxisome Proliferator Activated Receptor Gamma Ligand Rosiglitazone in Human Melanoma Cell Line A375

Abstract

Ligands of peroxisome proliferator-activated receptors (PPARs) have been demonstrated to be antitumorgenic in vitro and in vivo due to their antiproliferative, prodifferential, and antiangiogenic effects. The aim of this study is to evaluate the effects and mechanisms of PPARgamma ligand rosiglitazone (ROZ) on the growth, apoptosis, and differentiation in human melanoma cancer cell line A375. The effects of ROZ on A375 cell proliferation were measured by clonogenic assay, apoptosis and cell cycle kinetics by FACS with ROZ for 72 h, PPARgamma protein was detected by Western blot analysis and immunocytochemical staining, and PPARgamma mRNA expression by RT-PCR. The differentiation effect of ROZ was determined by measurement of melanin content and tyrosinase activity. The levels of Bcl-2, P53, p-ERK, and ERK were also detected by Western blot analysis. Inhibition of tumorigensis was observed in nude mice. ROZ inhibited colony formation and induced apoptosis in A375 cells, and the cells were arrested in G1 phase. This effect was associated with a decrease of the expression of Bcl-2 and increase of the expression of P53. ROZ also induced the differentiation in A375 cells. ROZ increased expression of PPARgamma and decreased the expression of ERK and p-ERK. Data in vivo showed that ROZ could inhibit tumorigensis in nude mice. These results demonstrated that ROZ inhibited growth of A375 cells via the induction of apoptosis, necrosis, and differentiation in a PPARgamma-dependent manner and might present a promising therapeutic approach in certain human maligancies.