Endothelin-1 induces vascular endothelial growth factor by increasing hypoxia-inducible factor-1alpha in ovarian carcinoma cells.
Angiogenesis is an essential prerequisite for tumor growth, invasion, and metastasis. In ovarian carcinoma cells, endothelin-1 (ET-1) stimulates the secretion of vascular endothelial growth factor (VEGF), a major mediator of tumor angiogenesis. In OVCA 433 and HEY ovarian carcinoma cell lines, ET-1 treatment increases VEGF mRNA expression and induces VEGF protein levels in a time- and dose-dependent fashion, and do so to a greater extent under hypoxic conditions. ET-1 also increases hypoxia-inducible factor-1alpha (HIF-1alpha) accumulation and activates the HIF-1 transcription complex under both normoxic and hypoxic conditions, suggesting a role for HIF-1 in the induction of VEGF expression. These effects are inhibited by the selective ET(A) receptor (ET(A)R) antagonist, BQ123. The ET-1-induced increase in HIF-1alpha protein levels is due to the enhanced HIF-1alpha stabilization. These results implicate HIF-1alpha in the induction of VEGF expression in ET-1-stimulated ovarian carcinoma cells, and provide a mechanism whereby ET-1 acting selectively through ET(A)R can interact with the HIF-1alpha-dependent machinery of angiogenesis. Our results suggest that new therapeutic strategies using specific ET(A)R antagonists could provide an additional approach to the treatment of ovarian carcinoma by inhibiting neovascularization as well as tumor cell growth.
Spinella
Francesca
F
Laboratory of Molecular Pathology, Regina Elena Cancer Institute, 00158 Rome, Italy.
Rosanò
Laura
L
Di Castro
Valeriana
V
Natali
Pier Giorgio
PG
Bagnato
Anna
A
D015687:Cell Hypoxia / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D017931:DNA Primers; D016228:Endothelial Growth Factors / Q000235:genetics*; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007700:Kinetics; D008222:Lymphokines / Q000235:genetics*; D010051:Ovarian Neoplasms; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D017931:DNA Primers; D016228:Endothelial Growth Factors; D019332:Endothelin-1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors