Insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades involving GSK-3beta inhibition and Ras activation

Oncogene. 2001 Jan 11;20(2):252-9. doi: 10.1038/sj.onc.1204064.

Abstract

We examined the interplay between the insulin/IGF-1- and beta-catenin-regulated pathways, both of which are suspected to play a role in hepatocarcinogenesis. Insulin and IGF-1 stimulated the transcription of a Lef/Tcf-dependent luciferase reporter gene by 3-4-fold in HepG2 cells. This stimulation was mediated through the activation of phosphatidylinositol 3-kinase (PI 3-K)/Akt and the inhibition of glycogen synthase kinase-3beta (GSK-3beta) since the effects of insulin and IGF-1 were inhibited by dominant-negative mutants of PI 3-K or Akt and an uninhibitable GSK-3beta. Together with inhibiting GSK-3beta, insulin and IGF-1 increased the cytoplasmic levels of beta-catenin. The PI 3-K/Akt/GSK-3beta pathway was not the sole to mediate insulin and IGF-1 stimulation of Lef/Tcf-dependent transcription. The Ras signalling pathway was also required as (i) the stimulatory effects of insulin and IGF-1 were inhibited by dominant-negative Ras or the MEK1 inhibitor PD98059 and (ii) activated Ha-Ras or constitutively active MEK1 synergized with catalytically inactive GSK-3beta to stimulate Lef/Tcf-dependent transcription. This study provides the first evidence that insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades bifurcating downstream of PI 3-K and involving GSK-3beta inhibition and Ras activation. These findings demonstrate for the first time the ability of insulin and IGF-1 to activate the beta-catenin pathway in hepatoma cells and thereby provide new insights into the role of these factors in hepatocarcinogenesis.

MeSH terms

  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Carcinoma, Hepatocellular / metabolism
  • Cell Division / drug effects
  • Cytoskeletal Proteins / drug effects
  • Cytoskeletal Proteins / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Genes, Reporter
  • Genes, ras*
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinases
  • Humans
  • Insulin / metabolism*
  • Insulin / pharmacology
  • Insulin-Like Growth Factor I / metabolism*
  • Insulin-Like Growth Factor I / pharmacology
  • Lymphoid Enhancer-Binding Factor 1
  • MAP Kinase Kinase 1
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mutation
  • Phosphatidylinositol 3-Kinases / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / drug effects
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction
  • Trans-Activators*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Tumor Cells, Cultured
  • beta Catenin

Substances

  • CTNNB1 protein, human
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Flavonoids
  • Insulin
  • Lymphoid Enhancer-Binding Factor 1
  • Proto-Oncogene Proteins
  • Trans-Activators
  • Transcription Factors
  • beta Catenin
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • Glycogen Synthase Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Glycogen Synthase Kinase 3
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • Mitogen-Activated Protein Kinase Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one