Statin-induced mevalonate pathway inhibition attenuates the growth of mesenchymal-like cancer cells that lack functional E-cadherin mediated cell cohesion.
Statin-induced mevalonate pathway inhibition attenuates the growth of mesenchymal-like cancer cells that lack functional E-cadherin mediated cell cohesion.
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DOI：
10.1038/srep07593
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发表时间：
2014-12-23
影响因子：
4.6
通讯作者：
Oltvai ZN
中科院分区：
文献类型：
--
作者：
Warita K;Warita T;Beckwitt CH;Schurdak ME;Vazquez A;Wells A;Oltvai ZN
降胆固醇药物他汀类药物对癌症干细胞和多种癌细胞具有抗肿瘤作用，在癌症动物模型中与现有的化疗药物具有很强的相加或协同作用，可能会降低人类的癌症发病率和癌症相关死亡率。然而，并不是所有的肿瘤细胞系都对他汀类药物敏感，临床试验表明，他汀类药物作为抗癌剂的结果好坏参半。在这里，我们表明他汀类药物诱导的细胞内胆固醇水平的降低与他汀类药物对癌细胞生长的抑制有关。此外，他汀类药物敏感性分离，胞浆中有丰富的波形蛋白表达，而细胞表面E-钙粘附素缺乏表达，这是间充质样细胞的特征。细胞表面E-钙粘附素的外源表达将他汀类药物敏感的细胞转化为部分耐药状态，这意味着他汀类药物的耐药部分依赖于肿瘤细胞获得上皮表型。由于转移性肿瘤细胞在转移级联反应的启动过程中经历了上皮到间质的转变，他汀类药物可能是一种有效的靶向最有可能扩散的细胞的方法。
The cholesterol reducing drugs, statins, exhibit anti-tumor effects against cancer stem cells and various cancer cell lines, exert potent additivity or synergy with existing chemotherapeutics in animal models of cancer and may reduce cancer incidence and cancer related mortality in humans. However, not all tumor cell lines are sensitive to statins, and clinical trials have demonstrated mixed outcomes regarding statins as anticancer agents. Here, we show that statin-induced reduction in intracellular cholesterol levels correlate with the growth inhibition of cancer cell lines upon statin treatment. Moreover, statin sensitivity segregates with abundant cytosolic vimentin expression and absent cell surface E-cadherin expression, a pattern characteristic of mesenchymal-like cells. Exogenous expression of cell surface E-cadherin converts statin- sensitive cells to a partially resistant state implying that statin resistance is in part dependent on the tumor cells attaining an epithelial phenotype. As metastasizing tumor cells undergo epithelial to mesenchymal transition during the initiation of the metastatic cascade, statin therapy may represent an effective approach to targeting the cells most likely to disseminate.
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影响因子：
6
作者：
Li, YC;Park, MJ;Kim, YN
通讯作者：
Kim, YN
影响因子：
5.2
作者：
Ginestier, Christophe;Monville, Florence;Charafe-Jauffret, Emmanuelle
通讯作者：
Charafe-Jauffret, Emmanuelle
影响因子：
4.8
作者：
Malenda, Agata;Skrobanska, Anna;Nowis, Dominika A.
通讯作者：
Nowis, Dominika A.
影响因子：
37.3
作者：
Chao YL;Shepard CR;Wells A
通讯作者：
Wells A
影响因子：
21.3
作者：
Sorrentino, Giovanni;Ruggeri, Naomi;Del Sal, Giannino
通讯作者：
Del Sal, Giannino