Vascular endothelial growth factor gene expression in colon cancer cells exposed to prostaglandin E2 is mediated by hypoxia-inducible factor 1

Cancer Res. 2003 May 1;63(9):2330-4.

Abstract

Prostaglandin E(2) (PGE(2)) has been implicated as an inducer of angiogenesis in human colon cancer. Here, we demonstrate that PGE(2) exposure induces the expression of vascular endothelial growth factor (VEGF) mRNA in HCT116 human colon carcinoma cells that is mediated by the transcriptional activator hypoxia-inducible factor 1 (HIF-1). PGE(2) exposure induces the phosphorylation of extracellular signal-regulated kinase (ERK) and AKT. Pharmacologic inhibition of ERK phosphorylation blocks the induction of VEGF mRNA and HIF-1alpha protein expression in response to PGE(2) stimulation. Inhibition of C-SRC tyrosine kinase activity also blocks PGE(2)-induced HIF-1alpha protein and VEGF mRNA expression without blocking ERK phosphorylation. In contrast, phosphorylation of AKT is dependent on ERK and C-SRC activity. Thus, the activity of multiple signal transduction pathways is required for the HIF-1-mediated induction of VEGF expression in colon cancer cells exposed to PGE(2).

Publication types

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

MeSH terms

  • CSK Tyrosine-Protein Kinase
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism*
  • Dinoprostone / pharmacology*
  • Endothelial Growth Factors / biosynthesis*
  • Endothelial Growth Factors / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / physiology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Intercellular Signaling Peptides and Proteins / biosynthesis*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Lymphokines / biosynthesis*
  • Lymphokines / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphorylation
  • Protein Serine-Threonine Kinases*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / biosynthesis
  • Transcription Factors / physiology*
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • src-Family Kinases

Substances

  • Endothelial Growth Factors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Intercellular Signaling Peptides and Proteins
  • Lymphokines
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Protein-Tyrosine Kinases
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • CSK protein, human
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • Dinoprostone