The elucidation of MPA-induoed inhibition of colorectal cancer growth by hormone replace replacement therapy

许多流行病学和实验研究表明，女性性激素可能会降低患结肠癌的风险。妇女健康倡议最近报告了一项随机对照试验的数据，该试验比较了绝经后妇女雌激素+孕激素和安慰剂的疗效。在这份报告中，结合马雌激素(CEE)和甲孕酮的联合治疗与结直肠癌的发病率显著降低有关，而单独使用CEE既不增加也不降低结直肠癌的发病率。然而，甲孕酮预防结直肠癌的确切机制仍有待充分研究。以人结肠癌细胞株HT29和HCT116为研究对象，研究了醋酸甲羟孕酮对人结肠癌细胞株体外生长的影响。通过细胞生长和WST-1实验观察醋酸甲羟孕酮的抗增殖作用。通过细胞周期分析，观察醋酸甲羟孕酮对细胞周期分布的影响。用Western印迹、免疫沉淀和细胞周期蛋白依赖性激酶检测细胞周期蛋白水平的变化。醋酸美托孕酮通过诱导G0/G1组分积聚抑制癌细胞的增殖。醋酸甲羟孕酮降低了细胞周期蛋白E的表达，增加了p21的表达，增强了p21与细胞周期蛋白依赖性激酶2的相互作用，最终抑制了其活性。醋酸甲羟孕酮通过调节细胞周期相关蛋白的表达和细胞周期蛋白依赖性蛋白2的活性发挥其抗增殖作用。这些结果应该有助于阐明醋酸甲羟孕酮对结肠癌风险的保护作用。

Numerous epidemiological and experimental studies have suggested the possible effect of female sex hormones against colon cancer risk. The Women's Health Initiative recently reported data from a randomized controlled trial that compared estrogen plus progestin with placebo in postmenpausal women. In this report, therapy with a combination of conjugated equine estrogen(CEE) plus MPA was associated with a significant decrease in the incidence of colorectal cancer, while therapy with CEE alone neither increased nor decreased the incidence of colorectal cancer. However, the precise mechanism by which MPA prevents colorectal cancer remains to be fully investigated. To investigate the effects of medroxyprogesterone acetate on colon cancer cells in vitro, HT29 and HCT116 human colon cancer cell lines were used in this study. Cell growth and WST-1 assays were performed to investigate the antiproliferative effect of medroxyprogesterone acetate. Cell cycle analysis was performed to investigate the effects of medroxyprogesterone acetate on cell cycle distribution. Western blot, immunoprecipitation and cyclin-dependent kinase assay were performed to investigate changes in the levels of cell cycle proteins.Medroxyprogesterone acetate inhibited proliferation of the cancer cells by inducing accumulation in the G0/G1 fraction. Medroxyprogesterone acetate decreased expression of cyclin E, increased expression of p21, and enhanced interaction of p21 with cyclin-dependent kinase2, eventually inhibiting its activity. Medroxyprogesterone acetate exerts its antiproliferative effect by modulating cell cycle-related protein expression and cyclin-dependent kinase 2 activity. These results should help to elucidate the protective effect of medroxyprogesterone acetate on colon cancer risk.