Activation of transcription factor Nrf2 by hepatitis C virus induces the cell-survival pathway.
Oxidative stress has been implicated in various human diseases, including the pathogenesis of hepatitis C virus (HCV). Previous studies have shown the induction of oxidative stress in cultured cells expressing HCV genes. The transcription factor Nrf2 is known to be activated in response to oxidative stress, but the mechanism of its activation is not clearly understood. In this study, we first determined the induction of Nrf2 and then investigated the mechanism of Nrf2 activation in human hepatoma cells infected with HCV (JFH-1). Our results showed the induction and nuclear translocation of Nrf2 in a time-dependent manner. The HCV-mediated activation of Nrf2 was abrogated in the presence of an antioxidant, PDTC (pyrrolidine dithiocarbamate), and a Ca(2+) chelator, BAPTA-AM [1,2-bis(aminophenoxy)ethane N,N,N,N-tetraacetic acid tetra(acetoxymethyl) ester], which suggests a role for both reactive oxygen species and Ca(2+) signalling in the Nrf2-activation process. By using inhibitors of cellular kinases, we showed further that HCV-mediated phosphorylation/activation of Nrf2 is mediated by the mitogen-activated protein (MAP) kinases p38 MAPK and janus kinase. We also observed enhanced phosphorylation of Akt and its downstream substrate Bad in HCV-infected cells. Furthermore, by using a small interfering RNA approach, our results suggest a potential role for HCV-mediated Nrf2 activation in the survival of HCV-infected cells, a condition favourable for liver oncogenesis. Taken together, these results provide an insight into the mechanisms by which HCV induces intracellular events relevant to chronic HCV infection.
Burdette
Dylan
D
Department of Microbiology and Immunology, H. M. Bligh Cancer Research Laboratories, Rosalind Franklin University of Medicine and Science, Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064, USA.
Olivarez
Mathew
M
Department of Microbiology and Immunology, H. M. Bligh Cancer Research Laboratories, Rosalind Franklin University of Medicine and Science, Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064, USA.
Waris
Gulam
G
Department of Microbiology and Immunology, H. M. Bligh Cancer Research Laboratories, Rosalind Franklin University of Medicine and Science, Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064, USA.
D020013:Calcium Signaling; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000737:chemistry; D002470:Cell Survival; D020868:Gene Silencing; D016174:Hepacivirus / Q000472:pathogenicity*; D022781:Hepatocytes / Q000821:virology*; D006801:Humans; D053613:Janus Kinase 1 / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D053613:Janus Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases