Endothelin-1 induces vascular endothelial growth factor by increasing hypoxia-inducible factor-1 alpha 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 (HIP-1alpha) accumulation and activates the HIP-1 transcription complex under both normoxic and hypoxic conditions, suggesting a role for HIP-1 in the induction of VEGF expression. These effects are inhibited by the selective ETA receptor (ETAR) antagonist, BQ123. The ET-1-induced increase in HIP-1alpha protein levels is due to the enhanced HIP-1alpha stabilization. These results implicate HIP-1alpha in the induction of VEGF expression in ET-1-stimulated ovarian carcinoma cells, and provide a mechanism whereby ET-1 acting selectively through ETAR can interact with the HIP-1alpha-dependent machinery of angiogenesis. Our results suggest that new therapeutic strategies using specific ETAR antagonists could provide an additional approach to the treatment of ovarian carcinoma by inhibiting neovascularization as well as tumor cell growth.