Document Detail


Bile acids promote HCV replication through the EGFR/ERK pathway in replicon-harboring cells.
MedLine Citation:
PMID:  21293096     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: 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.
CONCLUSION: 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:
John B Patton; David George; Kyeong-Ok Chang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-02-05
Journal Detail:
Title:  Intervirology     Volume:  54     ISSN:  1423-0100     ISO Abbreviation:  Intervirology     Publication Date:  2011  
Date Detail:
Created Date:  2011-10-11     Completed Date:  2012-02-29     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  0364265     Medline TA:  Intervirology     Country:  Switzerland    
Other Details:
Languages:  eng     Pagination:  339-48     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 S. Karger AG, Basel.
Affiliation:
Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kans. 66506, USA.
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MeSH Terms
Descriptor/Qualifier:
Antiviral Agents / pharmacology
Bile Acids and Salts / pharmacology*,  physiology
Cell Cycle
Cell Line
Chenodeoxycholic Acid / pharmacology
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors,  metabolism*
Genes, Reporter
Hepacivirus / physiology*
Hepatitis C / drug therapy
Humans
Interferon-alpha / pharmacology
Interphase
Luciferases, Renilla / biosynthesis,  genetics
Promoter Regions, Genetic
Quinazolines / pharmacology
Receptor, Epidermal Growth Factor / antagonists & inhibitors,  metabolism*
Transcriptional Activation
Tyrphostins / pharmacology
Viral Nonstructural Proteins / metabolism
Virus Replication*
Grant Support
ID/Acronym/Agency:
P20RR016443/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Antiviral Agents; 0/Bile Acids and Salts; 0/Interferon-alpha; 0/NS-5 protein, hepatitis C virus; 0/Quinazolines; 0/Tyrphostins; 0/Viral Nonstructural Proteins; 170449-18-0/tyrphostin AG 1478; 474-25-9/Chenodeoxycholic Acid; EC 1.13.12.5/Luciferases, Renilla; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases
Comments/Corrections

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