title: Fluvastatin interferes with hepatitis C virus replication via microtubule bundling and a doublecortin-like kinase-mediated mechanism.
abstract: 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).
authors.affiliation: Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma, Oklahoma City, Oklahoma, United States of America ; Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, University of Oklahoma, Oklahoma City, Oklahoma, United States of America ; Department of Veterans Affairs Medical Center, University of Oklahoma, Oklahoma City, Oklahoma, United States of America.
authors.forename: Naushad
authors.initials: N
authors.lastname: Ali
authors.forename: Heba
authors.initials: H
authors.lastname: Allam
authors.forename: Ted
authors.initials: T
authors.lastname: Bader
authors.forename: Randal
authors.initials: R
authors.lastname: May
authors.forename: Kanthesh M
authors.initials: KM
authors.lastname: Basalingappa
authors.forename: William L
authors.initials: WL
authors.lastname: Berry
authors.forename: Parthasarathy
authors.initials: P
authors.lastname: Chandrakesan
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Qu
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Weygant
authors.forename: Michael S
authors.initials: MS
authors.lastname: Bronze
authors.forename: Shahid
authors.initials: S
authors.lastname: Umar
authors.forename: Ralf
authors.initials: R
authors.lastname: Janknecht
authors.forename: Sripathi M
authors.initials: SM
authors.lastname: Sureban
authors.forename: Mark
authors.initials: M
authors.lastname: Huycke
authors.forename: Courtney W
authors.initials: CW
authors.lastname: Houchen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000821:virology; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000089742:Doublecortin-Like Kinases; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D000077340:Fluvastatin; C117347:DCLK1 protein, human; D000089742:Doublecortin-Like Kinases; D017346:Protein Serine-Threonine Kinases