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Journal of Virology, October 2009, p. 9663-9671, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.00872-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Hepatitis C Virus Core Protein and Cellular Protein HAX-1 Promote 5-Fluorouracil-Mediated Hepatocyte Growth Inhibition{triangledown}

Arup Banerjee,1,{dagger} Kousuke Saito,1,{dagger} Keith Meyer,1 Sutapa Banerjee,1 Malika Ait-Goughoulte,1 Ratna B. Ray,1,2 and Ranjit Ray1,3*

Departments of Internal Medicine,1 Pathology,2 Molecular Microbiology and Immunology, Saint Louis University, St. Louis, Missouri 631193

Received 30 April 2009/ Accepted 6 July 2009

Hepatitis C virus (HCV) often causes chronic infection and may lead to hepatocellular carcinoma (HCC). We have shown previously that HCV core protein has pleiotropic functions, including transcriptional regulation of a number of cellular genes, although the mechanism for gene regulation remains unclear. In this study, a mammalian two-hybrid screen identified a novel binding partner, HS1-associated protein X-1 (HAX-1), for HCV core protein from a human liver cDNA library. An association between HAX-1 and HCV core protein was further verified by confocal microscopy and coimmunoprecipitation in HepG2 cells expressing HCV core or full-length (FL) gene. Both HCV core protein and a chemotherapeutic agent for HCC, 5-flouorouracil (5-FU), are known to modulate p53. We examined here whether an association between core and HAX-1 has any functional relevance to p53 modulation in 5-FU-treated cells. For this, the role of HAX-1 on 5-FU treatment was examined in HepG2 cells expressing HCV core or FL gene using cell proliferation, p53 expression, and caspase activation analysis. Cells expressing HCV-core or FL gene were more susceptible to 5-FU-induced growth inhibition than control cells, whereas cell survival was enhanced after suppression of HAX-1 by small interfering RNA. Further, 5-FU-mediated p53 expression was reduced with concurrent HAX-1 suppression in core- or polyprotein-expressing cells compared to control HepG2 cells, and caspase-2 and -7 activities were diminished. On the other hand, HCV core protein did not play a detectable role in 5-FU-mediated caspase-7 activation in the absence of functional p53 in Hep3B or Huh-7 cells. These observations underscore an association between HCV core and HAX-1, which promotes 5-FU mediated p53-dependent caspase-7 activation and hepatocyte growth inhibition.

* Corresponding author. Mailing address: Division of Infectious Diseases and Immunology, Edward A. Doisy Research Center, 1100 S. Grand Blvd., 8th Floor, St. Louis, MO 63104. Phone: (314) 977-9034. Fax: (314) 771-3816. E-mail: rayr{at}slu.edu

{triangledown} Published ahead of print on 15 July 2009.

{dagger} A.B. and K.S. contributed equally to this study.

Journal of Virology, October 2009, p. 9663-9671, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.00872-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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