Cancer Research Institute, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
Biochem Biophys Res Commun. 2011 Mar 18;406(3):389-95. doi: 10.1016/j.bbrc.2011.02.052. Epub 2011 Feb 15.
Peroxisome proliferator-activated receptor gamma (PPARγ) agonists, including thiazolidinediones (TZDs), can induce anti-proliferation, differentiation, and apoptosis in various cancer cell types. This study investigated the mechanism of the anticancer effect of TZDs on human ovarian cancer. Six human ovarian cancer cell lines (NIH:OVCAR3, SKOV3, SNU-251, SNU-8, SNU-840, and 2774) were treated with the TZD, which induced dose-dependent inhibition of cell growth. Additionally, these cell lines exhibited various expression levels of PPARγ protein as revealed by Western blotting. Flow cytometry showed that the cell cycle was arrested at the G1 phase, as demonstrated by the appearance of a sub-G1 peak. This observation was corroborated by the finding of increased levels of Bax, p21, PARP, and cleaved caspase 3 in TGZ-treated cells. Interestingly, when we determined the effect of p53-induced growth inhibition in these three human ovarian cancer cells, we found that they either lacked p53 or contained a mutant form of p53. Furthermore, TGZ induced the expression of endogenous or exogenous p63 and p73 proteins and p63- or p73-directed short hairpin (si) RNAs inhibited the ability of TGZ to regulate expression of p21 in these cells. Thus, our results suggest that PPARγ ligands can induce growth suppression of ovarian cancer cells and mediate p63 and p73 expression, leading to enhanced growth inhibition and apoptosis. The tumor suppressive effects of PPARγ ligands may have applications for the treatment of ovarian cancer.
过氧化物酶体增殖物激活受体 γ（PPARγ）激动剂，包括噻唑烷二酮（TZDs），可以在各种癌细胞中诱导抗增殖、分化和凋亡。本研究探讨了 TZDs 对人卵巢癌细胞的抗癌作用机制。用 TZD 处理 6 个人卵巢癌细胞系（NIH：OVCAR3、SKOV3、SNU-251、SNU-8、SNU-840 和 2774），诱导细胞生长呈剂量依赖性抑制。此外，Western blot 显示这些细胞系表现出不同水平的 PPARγ 蛋白表达。流式细胞术显示细胞周期在 G1 期被阻滞，表现为亚 G1 峰的出现。这一观察结果得到了在 TGZ 处理的细胞中 Bax、p21、PARP 和 cleaved caspase 3 水平升高的证实。有趣的是，当我们确定 p53 诱导的这三种人卵巢癌细胞生长抑制的作用时，我们发现它们要么缺乏 p53，要么含有 p53 的突变形式。此外，TGZ 诱导内源性或外源性 p63 和 p73 蛋白的表达，p63 或 p73 靶向短发夹（si）RNA 抑制 TGZ 调节这些细胞中 p21 表达的能力。因此，我们的结果表明，PPARγ 配体可以诱导卵巢癌细胞生长抑制，并介导 p63 和 p73 的表达，从而增强生长抑制和凋亡。PPARγ 配体的肿瘤抑制作用可能应用于卵巢癌的治疗。
