Fluvastatin interferes with hepatitis C virus replication via microtubule bundling and a doublecortin-like kinase-mediated mechanism.
Fluvastatin interferes with hepatitis C virus replication via microtubule bundling and a doublecortin-like kinase-mediated mechanism.
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DOI：
10.1371/journal.pone.0080304
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Houchen CW
中科院分区：
文献类型：
--
作者：
Ali N;Allam H;Bader T;May R;Basalingappa KM;Berry WL;Chandrakesan P;Qu D;Weygant N;Bronze MS;Umar S;Janknecht R;Sureban SM;Huycke M;Houchen CW
丙型肝炎病毒(HCV)诱导的脂质代谢和细胞蛋白表达的改变参与了病毒的发病。降胆固醇药物他汀类药物对丙型肝炎病毒和多种癌症的多效性作用机制尚不清楚。我们研究了氟伐他汀(Flv)在丙型肝炎病毒诱导的肝细胞癌变过程中对微管相关和肿瘤干细胞标记物(CSC)、双皮质样激酶1(DCLK1)的影响。采用丙型肝炎病毒复制模型、癌细胞株和正常人肝细胞，观察他汀类药物的抗病毒和抗肿瘤作用。在表达丙型肝炎病毒的肝癌细胞中，FLV治疗导致微管束形成、细胞周期停滞和细胞DCLK1分布的改变。这些事件对肝源性肿瘤细胞的存活产生了不利影响，而不影响正常的人类肝细胞。在细胞培养中，在不损害ATP库和细胞活力的情况下，FLV下调了丙型肝炎病毒的复制。普伐他汀对丙型肝炎病毒复制、微管和癌细胞没有这些影响。在FLV治疗期间，调节肝脏动态平衡和提供丙型肝炎病毒基因组稳定性的miR-122水平保持在稳定状态，而DCLK1mRNA水平显著降低。我们进一步证明，随着DCLK1的过度表达，丙型肝炎病毒的复制增加。综上所述，除了对3-羟基-3-甲基谷氨酸-辅酶A还原酶(HMGCR)的抑制作用外，Flv对微管及其结合伴侣DCLK1的独特作用可能有助于其抗丙型肝炎病毒和抗肿瘤活性。
Hepatitis C virus (HCV)-induced alterations in lipid metabolism and cellular protein expression contribute to viral pathogenesis. The mechanism of pleiotropic actions of cholesterol-lowering drugs, statins, against HCV and multiple cancers are not well understood. We investigated effects of fluvastatin (FLV) on microtubule-associated and cancer stem cell marker (CSC), doublecortin-like kinase 1 (DCLK1) during HCV-induced hepatocarcinogenesis. HCV replication models, cancer cell lines and normal human hepatocytes were used to investigate the antiviral and antitumor effects of statins. FLV treatment resulted in induction of microtubule bundling, cell-cycle arrest and alterations in cellular DCLK1 distribution in HCV-expressing hepatoma cells. These events adversely affected the survival of liver-derived tumor cells without affecting normal human hepatocytes. FLV downregulated HCV replication in cell culture where the ATP pool and cell viability were not compromised. Pravastatin did not exhibit these effects on HCV replication, microtubules and cancer cells. The levels of miR-122 that regulates liver homeostasis and provides HCV genomic stability remained at steady state whereas DCLK1 mRNA levels were considerably reduced during FLV treatment. We further demonstrated that HCV replication was increased with DCLK1 overexpression. In conclusion, unique effects of FLV on microtubules and their binding partner DCLK1 are likely to contribute to its anti-HCV and antitumor activities in addition to its known inhibitory effects on 3-hydroxy-3-methylglutary-CoA reductase (HMGCR).
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影响因子：
29.4
作者：
El-Serag HB
通讯作者：
El-Serag HB
影响因子：
56.9
作者：
Jopling, CL;Yi, MK;Sarnow, P
通讯作者：
Sarnow, P
影响因子：
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作者：
Ali, Naushad;Allam, Heba;Houchen, Courtney W.
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Houchen, Courtney W.
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5.4
作者：
Lai, Chao-Kuen;Jeng, King-Song;Lai, Michael M. C.
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Lai, Michael M. C.
影响因子：
30.8
作者：
Prokunina-Olsson, Ludmila;Muchmore, Brian;Tang, Wei;Pfeiffer, Ruth M.;Park, Heiyoung;Dickensheets, Harold;Hergott, Dianna;Porter-Gill, Patricia;Mumy, Adam;Kohaar, Indu;Chen, Sabrina;Brand, Nathan;Tarway, McAnthony;Liu, Luyang;Sheikh, Faruk;Astemborski, Jacquie;Bonkovsky, Herbert L.;Edlin, Brian R.;Howell, Charles D.;Morgan, Timothy R.;Thomas, David L.;Rehermann, Barbara;Donnelly, Raymond P.;O'Brien, Thomas R.
通讯作者：
O'Brien, Thomas R.