title: Bile acids promote HCV replication through the EGFR/ERK pathway in replicon-harboring cells.
abstract: OBJECTIVE
  Bile acids promoted the replication of hepatitis C virus (HCV) and compromised the anti-HCV effects of interferon-α (IFN-α) in replicon-harboring cells. To explore a potential mechanism for the observation, we studied the effects of bile acids on the epidermal growth factor receptor (EGFR) and the extracellular signal-regulated kinase (ERK) pathway in association with HCV replication in genotype 1a or 1b replicon-harboring cells.
  
  
  METHODS
  Replicon-harboring cells were treated with various bile acids, IFN-α and small molecule inhibitors either individually or combined together. The effects of these treatments were measured using cell cycle analysis, qRT-PCR, and Western blot analysis.
  
  
  RESULTS
  Bile acids induced the activation of EGFR/ERK pathway and extended S-phase of cells, which was correlated with the increased levels of viral replication. The inhibitors of EGFR (AG1478) or ERK (U0126) significantly mitigated the bile acid-mediated promotion of HCV replication. When AG1478 or U0126 were added to the treatment of bile acids and IFN-α, they were able to restore the anti-HCV effects of IFN-α.
  
  
  CONCLUSIONS
  Our data suggest that the addition of an EGFR or ERK inhibitor to the current IFN-α-based regimen may improve overall treatment efficacy by blocking the bile acid-mediated promotion of HCV replication.
authors.affiliation: Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kans. 66506, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Patton
authors.forename: David
authors.initials: D
authors.lastname: George
authors.forename: Kyeong-Ok
authors.initials: KO
authors.lastname: Chang
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000494:pharmacology* / Q000502:physiology; D002453:Cell Cycle; D002460:Cell Line; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017930:Genes, Reporter; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D007399:Interphase; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D011799:Quinazolines / Q000494:pharmacology; D015533:Transcriptional Activation; D020032:Tyrphostins / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D014779:Virus Replication; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001647:Bile Acids and Salts; D002635:Chenodeoxycholic Acid; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D016898:Interferon-alpha; D049410:Luciferases, Renilla; D011799:Quinazolines; D020032:Tyrphostins; D017361:Viral Nonstructural Proteins; C101044:RTKI cpd; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase