title: Insulin-induced mTOR activity exhibits anti-hepatitis C virus activity.
abstract: The mammalian target of rapamycin (mTOR) is one of the influential molecules for the anti-hepatitis C virus (HCV) action of interferon (IFN). IFN-induced mTOR activity, independent of phosphatidylinositol-3-kinase (PI3K) and Akt, is a critical factor for anti-HCV activity. mTOR activity is involved in signal transducers and activators of transcription (STAT)-1 phosphorylation and nuclear localization, and then double-stranded RNA-dependent protein kinase (PKR) is expressed in hepatocytes. Insulin (INS) is a major cytokine for metabolism and regulates the PI3K-Akt-mTOR signaling pathway in hepatocytes. Changes in mTOR activity have been reported in chronic HCV-infected patients with excess nutrition and INS resistance. Therefore, this experiment investigated whether INS increases anti-HCV activity via mTOR activity. This study used a genome-length HCV RNA (strain O of genotype 1b) replicon reporter system (OR6), derived from HuH7 cells. OR6 cells were pre-treated with rapamycin or LY294002 or siRNA, and the cells were treated with INS (0-300 nmol/l) or IFN (0-50 IU/ml) for 30 min to 48 h. The cells were lysed and analyses were carried out using the Renilla luciferase assay, western blotting or ELISA. INS induced the anti-HCV effects via mTOR activity, independently of STAT-1 tyrosine phosphorylation, in a dose- and time-dependent manner. INS-induced mTOR activation was found to be PI3K-Akt-dependent in OR6 cells. The combination of IFN and INS had an additive anti-HCV effect. The INS-induced mTOR activity was identified to be an anti-HCV signal independent of the STAT pathway in this study. mTOR activity may be associated with the HCV life cycle. Future studies should, therefore, attempt to identify new agents that activate mTOR to promote anti-HCV activity.
authors: Department of Gastroenterology and Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan. tourumura@hotmail.com
authors: Toru
authors: T
authors: Muraoka
authors: Tatsuki
authors: T
authors: Ichikawa
authors: Naota
authors: N
authors: Taura
authors: Hisamitsu
authors: H
authors: Miyaaki
authors: Shigeyuki
authors: S
authors: Takeshita
authors: Motohisa
authors: M
authors: Akiyama
authors: Satoshi
authors: S
authors: Miuma
authors: Eisuke
authors: E
authors: Ozawa
authors: Hajime
authors: H
authors: Isomoto
authors: Fuminao
authors: F
authors: Takeshima
authors: Kazuhiko
authors: K
authors: Nakao
mesh_terms: D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007372:Interferons / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D002867:Chromones; D007328:Insulin; D007372:Interferons; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one