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Thr 446 phosphorylation of PKR by HCV core protein deregulates G2/M phase in HCC cells

A Alisi1, R Mele, A Spaziani

  • 1Dipartimento di Medicina Interna e Sanità Pubblica (M.I.S.P.), University of L'Aquila, L'Aquila, Italy.

Journal of Cellular Physiology
|May 10, 2005
PubMed

Insights

Hepatitis C virus core protein causes cell cycle arrest in liver cancer cells, primarily through PKR pathway inactivation, impacting viral pathogenesis and interferon resistance.

Area of Science:

  • Hepatology
  • Virology
  • Molecular Biology

Background:

  • Hepatitis C virus (HCV) is a primary cause of liver cirrhosis and hepatocellular carcinoma (HCC).
  • HCV core protein influences cellular processes and contributes to HCC development.
  • Understanding HCV core protein's role in cell cycle regulation is crucial for targeting HCC pathogenesis.

Purpose of the Study:

  • To investigate the impact of HCV core protein expression on cell cycle progression in HCC cell lines.
  • To elucidate the specific molecular pathways involved in HCV core protein-induced cell cycle alterations.
  • To explore the implications of these effects on viral pathogenesis and treatment resistance.

Main Methods:

  • Cell cycle analysis using flow cytometry in HepG2 cells expressing HCV core protein.
  • Investigation of the roles of p53 and protein kinase R (PKR) in mediating G2/M phase arrest.
  • Analysis of PKR phosphorylation status and its correlation with eIF-2 phosphorylation.

Main Results:

  • HCV core protein expression led to significant accumulation of HCC cells in the G2/M phase.
  • p53 played a minor role, while PKR inactivation was critical for the observed G2/M arrest.
  • PKR phosphorylation at Thr 446 was elevated in HCC core-positive cells, disrupting mitosis.
  • HCV core protein upregulated PKR activity without increasing eIF-2 phosphorylation, suggesting alternative pathway involvement.

Conclusions:

  • HCV core protein disrupts cell cycle regulation, specifically inducing G2/M arrest via PKR-dependent mechanisms.
  • This disruption may contribute to hepatocellular carcinoma development and resistance to interferon therapy.
  • Alternative PKR-mediated pathways are implicated in HCV pathogenesis and cell cycle deregulation.

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