Simvastatin and metformin inhibit cell growth in hepatitis C virus infected cells via mTOR increasing PTEN and autophagy.
Simvastatin and metformin inhibit cell growth in hepatitis C virus infected cells via mTOR increasing PTEN and autophagy.
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DOI：
10.1371/journal.pone.0191805
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Romero-Gómez M
中科院分区：
文献类型：
--
作者：
Del Campo JA;García-Valdecasas M;Gil-Gómez A;Rojas Á;Gallego P;Ampuero J;Gallego-Durán R;Pastor H;Grande L;Padillo FJ;Muntané J;Romero-Gómez M
丙型肝炎病毒（HCV）感染与肝细胞癌（HCC）发生风险增加有关，而二甲双胍(M)和他汀类药物治疗似乎可以预防HCC的发生。在这项工作中，我们的目标是确定二甲双胍和辛伐他汀(S)预防肝癌的机制。用HCV颗粒感染Huh7.5细胞，用M+S处理。M+S治疗人原代肝细胞。两种药物治疗均抑制Huh7.5细胞生长和HCV感染。在未感染的细胞中，S增加了翻译控制肿瘤蛋白（TCTP）和磷酸酶和紧张素同源物（PTEN）蛋白，而M抑制了雷帕霉素靶蛋白（mTOR）和TCTP。辛伐他汀和二甲双胍联合用药可下调mTOR和TCTP，而PTEN升高。HCV感染细胞mTOR、TCTP、p62和轻链3BII （LC3BII）升高，PTEN降低。S+M处理增加Huh7.5细胞PTEN、p62和LC3BII。在人原代肝细胞中，二甲双胍治疗抑制mTOR和PTEN，但上调p62、LC3BII和Caspase 3。综上所述，辛伐他汀和二甲双胍在体外抑制细胞生长和HCV感染。在人肝细胞中，二甲双胍增加了细胞死亡标志物。这些发现提示M+S治疗可用于hcv相关肝细胞癌的治疗性预防。
Hepatitis C virus (HCV) infection has been related to increased risk of development of hepatocellular carcinoma (HCC) while metformin (M) and statins treatment seemed to protect against HCC development. In this work, we aim to identify the mechanisms by which metformin and simvastatin (S) could protect from liver cancer. Huh7.5 cells were infected with HCV particles and treated with M+S. Human primary hepatocytes were treated with M+S. Treatment with both drugs inhibited Huh7.5 cell growth and HCV infection. In non-infected cells S increased translational controlled tumor protein (TCTP) and phosphatase and tensin homolog (PTEN) proteins while M inhibited mammalian target of rapamycin (mTOR) and TCTP. Simvastatin and metformin co-administered down-regulated mTOR and TCTP, while PTEN was increased. In cells infected by HCV, mTOR, TCTP, p62 and light chain 3B II (LC3BII) were increased and PTEN was decreased. S+M treatment increased PTEN, p62 and LC3BII in Huh7.5 cells. In human primary hepatocytes, metformin treatment inhibited mTOR and PTEN, but up-regulated p62, LC3BII and Caspase 3. In conclusion, simvastatin and metformin inhibited cell growth and HCV infection in vitro. In human hepatocytes, metformin increased cell-death markers. These findings suggest that M+S treatment could be useful in therapeutic prevention of HCV-related hepatocellular carcinoma.
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影响因子：
3.7
作者：
Saito T;Chiba T;Yuki K;Zen Y;Oshima M;Koide S;Motoyama T;Ogasawara S;Suzuki E;Ooka Y;Tawada A;Tada M;Kanai F;Takiguchi Y;Iwama A;Yokosuka O
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Yokosuka O
影响因子：
13.5
作者：
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Guan, Xin-Yuan
影响因子：
4.2
作者：
Cai, Xianbin;Hu, Xi;Jing, Xubin
通讯作者：
Jing, Xubin
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影响因子：
4.8
作者：
Peng, Lu;Liang, Dongyu;Yuan, Zhenghong
通讯作者：
Yuan, Zhenghong
影响因子：
5.7
作者：
Roudier, Emilie;Mistafa, Oras;Stenius, Ulla
通讯作者：
Stenius, Ulla