Ursodeoxycholic acid inhibits the proliferation of colon cancer cells by regulating oxidative stress and cancer stem-like cell growth.
Ursodeoxycholic acid inhibits the proliferation of colon cancer cells by regulating oxidative stress and cancer stem-like cell growth.
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DOI：
10.1371/journal.pone.0181183
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Kim YJ
中科院分区：
文献类型：
--
作者：
Kim EK;Cho JH;Kim E;Kim YJ
活性氧（ROS）的调控是癌症治疗的一个治疗靶点。先前的研究表明熊去氧胆酸（UDCA）抑制结肠癌细胞的增殖。本研究的目的是评估UDCA作为ROS调控的直接结果对结肠癌细胞增殖的影响。UDCA对结肠癌细胞系（HT29和HCT116）进行处理。用细胞计数仪测定细胞总数和死亡细胞数。采用异硫氰酸-溴脱氧尿苷荧光素流动试剂盒分析细胞周期变化。暴露于UDCA后，采用western blotting检测p27、p21、CDK2、CDK4和CDK6蛋白水平，采用qRT-PCR检测mRNA水平。采用荧光活化细胞分选法（FACS）对细胞内ROS进行染色检测。肿瘤球培养产生结肠癌干细胞样细胞系，UDCA处理7天。显微镜下测定肿瘤球总数。我们发现UDCA降低了结肠癌细胞总数，但没有增加死亡细胞的数量。UDCA抑制结肠癌细胞G1/S和G2/M过渡期。UDCA诱导细胞周期抑制剂如p27和p21的表达。然而，UDCA抑制了CDK2、CDK4和CDK6的水平。UDCA调节结肠癌细胞内ROS生成，诱导Erk1/2活化。最后，UDCA抑制结肠癌干细胞样细胞的形成。我们的研究结果表明，UDCA通过调节结肠癌细胞和结肠癌干细胞样细胞的氧化应激来抑制增殖。
The regulation of reactive oxygen species (ROS) exists as a therapeutic target for cancer treatments. Previous studies have shown that ursodeoxycholic acid (UDCA) suppresses the proliferation of colon cancer cells. The aim of this study was to evaluate the effect of UDCA upon the proliferation of colon cancer cells as a direct result of the regulation of ROS. Colon cancer cell lines (HT29 and HCT116) were treated with UDCA. The total number of cells and the number of dead cells were determined using cell counters. A fluorescein isothiocyanate-bromodeoxyuridine flow kit was used to analyze cell cycle variations. Upon exposure to UDCA, the protein levels of p27, p21, CDK2, CDK4 and CDK6 were determined using western blotting, and qRT-PCR was used to determine levels of mRNA. We preformed dichlorofluorescindiacetate (DCF-DA) staining to detect alteration of intracellular ROS using fluorescence activated cell sorting (FACS). Colon cancer stem-like cell lines were generated by tumorsphere culture and treated with UDCA for seven days. The total number of tumorspheres was determined using microscopy. We found that UDCA reduced the total number of colon cancer cells, but did not increase the number of dead cells. UDCA inhibited the G1/S and G2/M transition phases in colon cancer cells. UDCA induced expression of cell cycle inhibitors such as p27 and p21. However, it was determined that UDCA suppressed levels of CDK2, CDK4, and CDK6. UDCA regulated intracellular ROS generation in colon cancer cells, and induced activation of Erk1/2. Finally, UDCA inhibited formation of colon cancer stem-like cells. Our results indicate that UDCA suppresses proliferation through regulation of oxidative stress in colon cancer cells, as well as colon cancer stem-like cells.
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