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Activation of transcription factor Nrf2 by hepatitis C virus induces cell survival pathway

Rosalind Franklin University of Medicine and Science

¹ E-mail: gulam.waris{at}rosalindfranklin.edu

Oxidative stress has been implicated in various human diseases including in 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 Ca2+ chelator, BAPTA-AM (1, 2-bis (aminophenoxy)ethane N,N,N,N-tetraacetic acid-tetra (acetoxymethyl) ester), which suggest a role of both reactive oxygen species (ROS) and Ca2+ signaling in Nrf2 activation process. Using the inhibitors of cellular kinases, we further show that HCV-mediated phosphorylation/activation of Nrf2 is mediated by mitogen-activated protein (MAP) kinases, p38 MAPK, and janus kinase (JNK). We also observed the enhanced phosphorylation of Akt and its downstream substrate Bad in HCV-infected cells. Furthermore, using a siRNA approach our results suggest a potential role of HCV-mediated Nrf2 activation in the survival of HCV-infected cells, a condition favorable for liver oncogenesis. Taken together, these results provide an insight into the mechanisms by which HCV induces intracellular events relevant to chronic HCV infection.

Received 10 June 2009; accepted 29 October 2009.