Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells

J Biol Chem. 2002 Oct 11;277(41):38205-11. doi: 10.1074/jbc.M203781200. Epub 2002 Jul 30.

Abstract

Stimulation of human colon cancer cells with insulin-like growth factor 1 (IGF-1) induces expression of the VEGF gene, encoding vascular endothelial growth factor. In this article we demonstrate that exposure of HCT116 human colon carcinoma cells to IGF-1 induces the expression of HIF-1 alpha, the regulated subunit of hypoxia-inducible factor 1, a known transactivator of the VEGF gene. In contrast to hypoxia, which induces HIF-1 alpha expression by inhibiting its ubiquitination and degradation, IGF-1 did not inhibit these processes, indicating an effect on HIF-1 alpha protein synthesis. IGF-1 stimulation of HIF-1 alpha protein and VEGF mRNA expression was inhibited by treating cells with inhibitors of phosphatidylinositol 3-kinase and MAP kinase signaling pathways. These inhibitors also blocked the IGF-1-induced phosphorylation of the translational regulatory proteins 4E-BP1, p70 S6 kinase, and eIF-4E, thus providing a mechanism for the modulation of HIF-1 alpha protein synthesis. Forced expression of a constitutively active form of the MAP kinase kinase, MEK2, was sufficient to induce HIF-1 alpha protein and VEGF mRNA expression. Involvement of the MAP kinase pathway represents a novel mechanism for the induction of HIF-1 alpha protein expression in human cancer cells.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Carcinoma / metabolism*
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins
  • Colonic Neoplasms / metabolism*
  • Endothelial Growth Factors / genetics
  • Endothelial Growth Factors / metabolism*
  • Enzyme Inhibitors / metabolism
  • Eukaryotic Initiation Factor-4E / metabolism
  • Gene Expression Regulation
  • Humans
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Insulin-Like Growth Factor I / metabolism*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Lymphokines / genetics
  • Lymphokines / metabolism*
  • MAP Kinase Kinase 2
  • MAP Kinase Signaling System / physiology*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoproteins / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • Repressor Proteins / metabolism
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Ubiquitin / metabolism
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • Endothelial Growth Factors
  • Enzyme Inhibitors
  • Eukaryotic Initiation Factor-4E
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Intercellular Signaling Peptides and Proteins
  • Lymphokines
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoproteins
  • Repressor Proteins
  • Transcription Factors
  • Ubiquitin
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Insulin-Like Growth Factor I
  • MAP2K2 protein, human
  • Protein-Tyrosine Kinases
  • Ribosomal Protein S6 Kinases, 70-kDa
  • MAP Kinase Kinase 2
  • Mitogen-Activated Protein Kinase Kinases