Lithium-mediated downregulation of PKB/Akt and cyclin E with growth inhibition in hepatocellular carcinoma cells

Int J Cancer. 2005 Jul 20;115(6):903-10. doi: 10.1002/ijc.20972.

Abstract

We studied in vitro effects of glycogen synthase kinase 3beta (GSK3beta)-inhibitor lithium on the growth of hepatocellular carcinoma (HCC) cells. Lithium induced strong growth inhibition (> 70%) in 75% (n = 9 of 12) of cell lines, apparently independent from the status of major genes that are mutated in HCC including p53, p16(INK4a), beta-catenin and Axin1. Comparative studies with a growth-sensitive Huh7 and growth-resistant Hep40 cell lines showed that lithium induces growth arrest in Huh7 cells but not in Hep40 cells. Lithium induced the accumulation of N-terminally phosphorylated inactive form of GSK3beta with concomitant increase in beta-catenin and beta-catenin/TCF transcriptional activity in both cell lines. This suggests that lithium-mediated HCC growth inhibition is independent of its well-known stimulatory effect on Wnt-beta-catenin signaling. The main differences between Huh7 and Hep40 responses to lithium treatment were observed at the levels PKB/Akt and cyclin E proteins. Lithium induced depletion of both proteins in growth-sensitive Huh7, but not in growth-resistant Hep40 cells. PKB/Akt and Cyclin E are 2 major proteins that are known to be constitutively active in HCC. The targeting of both proteins with lithium may be the main reason why most HCC cells are responsive to lithium-mediated growth inhibition, independent of their p53, retinoblastoma and Wnt-beta-catenin pathways. The exploration of molecular mechanisms involved in lithium-mediated growth inhibition in relation with PKB/Akt and cyclin E downregulation may provide new insights for therapy of liver tumors.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Hepatocellular / metabolism*
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Cyclin E / metabolism*
  • Cytoskeletal Proteins / metabolism
  • Down-Regulation
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Lithium / pharmacology*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Trans-Activators / metabolism
  • beta Catenin

Substances

  • CTNNB1 protein, human
  • Cyclin E
  • Cytoskeletal Proteins
  • Proto-Oncogene Proteins
  • Trans-Activators
  • beta Catenin
  • Lithium
  • AKT1 protein, human
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3