RT Journal Article
SR Electronic
T1 Vascular Endothelial Growth Factor Gene Expression in Colon Cancer Cells Exposed to Prostaglandin E<sub>2</sub> Is Mediated by Hypoxia-inducible Factor 1
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 2330
OP 2334
VO 63
IS 9
A1 Fukuda, Ryo
A1 Kelly, Brian
A1 Semenza, Gregg L.
YR 2003
UL http://cancerres.aacrjournals.org/content/63/9/2330.abstract
AB Prostaglandin E2 (PGE2) has been implicated as an inducer of angiogenesis in human colon cancer. Here, we demonstrate that PGE2 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). PGE2 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-1α protein expression in response to PGE2 stimulation. Inhibition of C-SRC tyrosine kinase activity also blocks PGE2-induced HIF-1α 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 PGE2. ©2003 American Association for Cancer Research.