The chemopreventive agent ursodeoxycholic acid inhibits proliferation of colon carcinoma cells by suppressing c-Myc expression
The chemopreventive agent ursodeoxycholic acid inhibits proliferation of colon carcinoma cells by suppressing c-Myc expression
复制标题
DOI：
10.1097/cej.0b013e32834ef16f
复制
发表时间：
2012-09-01
影响因子：
2.4
通讯作者：
Hanski, Christoph
中科院分区：
文献类型：
--
作者：
Peiro-Jordan, Roser;Krishna-Subramanian, Santosh;Hanski, Christoph
熊去氧胆酸（UDCA）可以预防化学和结肠炎相关的结肠癌，其机制尚不清楚。化学预防作用背后的一个过程可能是UDCA对增殖的抑制。为了阐明UDCA的抗增殖机制，我们使用p53（wt）结肠癌细胞系HCT8和HCT116。udca诱导的增殖抑制是可逆的，与s期减少和G1期细胞数量增加有关，但与细胞凋亡或衰老无关。该治疗抑制了c-Myc蛋白的表达，并因此抑制了包括CDK4和CDK6在内的几种细胞周期调节分子的表达。以HCT8细胞系为模型，我们发现UDCA在蛋白水平上抑制c-Myc。单独抑制c-Myc或同时抑制CDK4和CDK6激酶足以抑制细胞增殖。总之，我们确定c-Myc是结肠癌细胞中UDCA的主要靶点。c-Myc蛋白的降解降低了细胞周期调节因子CDK4和CDK6的表达，从而可逆地减缓了细胞周期。抑制这些促增殖分子可能是UDCA对结肠癌细胞抗增殖作用的初始机制。欧洲癌症预防杂志（英文版）：413-422 (C) 2012。
Ursodeoxycholic acid (UDCA) can prevent chemical and colitis-associated colon carcinogenesis by unknown mechanism(s). One of the processes underlying the chemopreventive action could be the inhibition of proliferation by UDCA. To clarify the antiproliferative mechanism of UDCA, we used p53(wt) colon carcinoma cell lines HCT8 and HCT116. UDCA-induced inhibition of proliferation was reversible and was associated with a decrease of the S-phase and an increase of G1 phase population, but not with apoptosis or senescence. The treatment suppressed the expression of c-Myc protein and, as a consequence, of several cell cycle regulatory molecules, including CDK4 and CDK6. Using the HCT8 cell line as a model, we show that UDCA suppresses c-Myc at the protein level. The suppression of c-Myc alone or a simultaneous suppression of CDK4 and of CDK6 kinase is sufficient to inhibit cell proliferation. In sum, we identified c-Myc as a primary UDCA target in colon carcinoma cells. The degradation of c-Myc protein decreases the expression of the cell cycle regulators CDK4 and CDK6, which reversibly slows down the cell cycle. The suppression of these proproliferatory molecules is the likely initial mechanism of antiproliferatory action of UDCA on colon cancer cells. European Journal of Cancer Prevention 21:413-422 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.