Smith Aaron G, Beaumont Kimberley A, Smit Darren J, Thurber Amy E, Cook Anthony L, Boyle Glen M, Parsons Peter G, Sturm Richard A, Muscat George E O
The University of Queensland, Institute for Molecular Bioscience, Qld 4072, Australia.
Int J Biochem Cell Biol. 2009 Apr;41(4):844-52. doi: 10.1016/j.biocel.2008.08.037. Epub 2008 Sep 6.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the nuclear hormone receptor (NHR) superfamily of ligand-activated transcriptional regulators. Accumulating evidence suggests that PPARgamma 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 PPARgamma modulators in human melanoma cell lines. Ablation of PPARgamma 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 PPARgamma. The mechanisms underlying the anti-proliferative effects of PPARgamma in melanoma cells involve the regulation of expression of a number of critical cell cycle genes and beta-catenin. Moreover, our data indicate that PPARgamma modulates Wnt/beta-catenin mediated signalling in melanoma cells in an agonist dependent manner.
过氧化物酶体增殖物激活受体γ（PPARγ）是核激素受体（NHR）超家族中配体激活的转录调节因子成员。越来越多的证据表明，噻唑烷二酮类（TZDs）等PPARγ激动剂可能被证明是有用的抗癌药物，在包括黑色素瘤在内的一系列癌细胞类型中表现出抗增殖和/或促凋亡作用，然而，这种作用的潜在机制仍不清楚。我们已经证明了全效和部分PPARγ调节剂在人黑色素瘤细胞系中的抗增殖作用。通过小干扰RNA（siRNA）介导的机制消除MM96L黑色素瘤细胞系中的PPARγ表达，会减弱这些药物的抗增殖作用，这表明这种作用是由PPARγ直接介导的。PPARγ在黑色素瘤细胞中抗增殖作用的潜在机制涉及许多关键细胞周期基因和β-连环蛋白表达的调节。此外，我们的数据表明，PPARγ以激动剂依赖的方式调节黑色素瘤细胞中Wnt/β-连环蛋白介导的信号传导。
