Endothelin-1 induces vascular endothelial growth factor by increasing hypoxia-inducible factor-1α in ovarian carcinoma cells

Francesca Spinella, Laura Rosanò, Valeriana Di Castro, Pier Giorgio Natali, Anna Bagnato

Research output: Contribution to journalArticle

192 Citations (Scopus)

Abstract

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-1α (HIF-1α) 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 ETA receptor (ETAR) antagonist, BQ123. The ET-1-induced increase in HIF-1α protein levels is due to the enhanced HIF-1α stabilization. These results implicate HIF-1α 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 HIF-1α- 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.

Original languageEnglish
Pages (from-to)27850-27855
Number of pages6
JournalJournal of Biological Chemistry
Volume277
Issue number31
DOIs
Publication statusPublished - Aug 2 2002

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Hypoxia-Inducible Factor 1
Endothelin-1
Vascular Endothelial Growth Factor A
Cells
Carcinoma
Tumors
Neoplasms
Cell growth
Transcription
Growth
Machinery
Proteins
Stabilization
Neoplasm Metastasis
Cell Line
Messenger RNA

ASJC Scopus subject areas

  • Biochemistry

Cite this

Endothelin-1 induces vascular endothelial growth factor by increasing hypoxia-inducible factor-1α in ovarian carcinoma cells. / Spinella, Francesca; Rosanò, Laura; Di Castro, Valeriana; Natali, Pier Giorgio; Bagnato, Anna.

In: Journal of Biological Chemistry, Vol. 277, No. 31, 02.08.2002, p. 27850-27855.

Research output: Contribution to journalArticle

Spinella, Francesca ; Rosanò, Laura ; Di Castro, Valeriana ; Natali, Pier Giorgio ; Bagnato, Anna. / Endothelin-1 induces vascular endothelial growth factor by increasing hypoxia-inducible factor-1α in ovarian carcinoma cells. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 31. pp. 27850-27855.
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