Statins induce mammalian target of rapamycin (mTOR)-mediated inhibition of Akt signaling and sensitize p53-deficient cells to cytostatic drugs
Statins induce mammalian target of rapamycin (mTOR)-mediated inhibition of Akt signaling and sensitize p53-deficient cells to cytostatic drugs
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DOI：
10.1158/1535-7163.mct-06-0352
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发表时间：
2006-11-01
影响因子：
5.7
通讯作者：
Stenius, Ulla
中科院分区：
文献类型：
--
作者：
Roudier, Emilie;Mistafa, Oras;Stenius, Ulla
降胆固醇他汀类药物已被证明在不同模型中具有抗癌作用，并使人类肿瘤细胞对细胞抑制药物敏感。我们研究了他汀类药物对 Akt/蛋白激酶 B 信号传导的影响以及细胞抑制剂的增敏作用。研究发现，在 HepG2、A549 和 H 1299 细胞中，普伐他汀和阿托伐他汀以 mTOR 依赖性方式抑制胰岛素和细胞抑制剂诱导的 Akt 磷酸化和核转位。他汀类药物还诱导胰岛素受体底物 1 的 mTOR 依赖性磷酸化。在 p53 野生型细胞（HepG2 和 A549）中，用他汀类药物预处理不会使细胞对诱导 p53 稳定的浓度的依托泊苷敏感。与我们之前的数据一致，他汀类药物被发现可以减弱依托泊苷诱导的 p53 反应。然而，通过 RNA 干扰沉默 p53 可以挽救敏化作用。我们还发现，在 p53 缺陷细胞系 (H1299) 中，阿托伐他汀预处理可使细胞对依托泊苷、阿霉素和 5-氟尿嘧啶敏感，并增加细胞凋亡水平。总而言之，这些数据表明 mTOR 依赖性、他汀类药物诱导的 Akt 磷酸化和核易位抑制使细胞对细胞生长抑制药物敏感。然而，在 p53 感受态细胞中，这种效应可以通过他汀类药物破坏 p53 的能力来抵消。
Cholesterol-lowering statins have been shown to have anticancer effects in different models and sensitize human tumor cells to cytostatic drugs. We have investigated the effect of statins on Akt/protein kinase B signaling and the sensitizing effect of cytostatic drugs. It was found that insulin - and cytostatic drug-induced Akt phosphorylation and nuclear translocation was inhibited by pravastatin and atorvastatin in HepG2, A549, and H 1299 cells in an mTOR-dependent manner. Statins also induced mTOR-dependent phosphorylation of insulin receptor substrate 1. In p53 wild-type cells (HepG2 and A549), pretreatment with statins did not sensitize cells to etoposide in concentrations which induced p53 stabilization. In line with our previous data, statins were found to attenuate the etoposide-induced p53 response. However, silencing p53 by RNA interference rescued the sensitizing effect. We also show that in a p53-deficient cell line (H1299), pretreatment with atorvastatin sensitized cells to etoposide, doxorubicin, and 5-fluorouracil and increased the level of apoptosis. Taken together, these data suggest that a mTOR-dependent, statin-induced inhibition of Akt phosphorylation and nuclear translocation sensitizes cells to cytostatic drugs. However, this effect can be counteracted in p53 competent cells by the ability of statins to destabilize p53.