Polo-like kinase-1 mediates hepatitis C virus-induced cell migration, a drug target for liver cancer

Life Sci Alliance. 2023 Aug 30;6(11):e202201630. doi: 10.26508/lsa.202201630. Print 2023 Nov.

Abstract

Polo-like kinase 1 (PLK1) is a regulator of cell mitosis and cytoskeletal dynamics. PLK1 overexpression in liver cancer is associated with tumour progression, metastasis, and vascular invasion. Hepatitis C virus (HCV) NS5A protein stimulates PLK1-mediated phosphorylation of host proteins, so we hypothesised that HCV-PLK1 interactions might be a mechanism for HCV-induced liver cancer. We used a HCV cell-culture model (Jc1) to investigate the effects of virus infection on the cytoskeleton. In HCV-infected cells, a novel posttranslational modification in β-actin was observed with phosphorylation at Ser239. Using in silico and in vitro approaches, we identified PLK1 as the mediating kinase. In functional experiments with a phosphomimetic mutant form of β-actin, Ser239 phosphorylation influences β-actin polymerization and distribution, resulting in increased cell motility. The changes were prevented by treating cells with the PLK1 inhibitor volasertib. In HCV-infected hepatocytes, increased cell motility contributes to cancer cell migration, invasion, and metastasis. PLK1 is an important mediator of these effects and early treatment with PLK1 inhibitors may prevent or reduce HCC progression, particularly in people with HCV-induced HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins
  • Carcinoma, Hepatocellular* / genetics
  • Cell Movement / genetics
  • Hepacivirus
  • Hepatitis C*
  • Humans
  • Liver Neoplasms* / genetics
  • Polo-Like Kinase 1

Substances

  • Actins