Endothelin-1 stimulates cyclooxygenase-2 expression in ovarian cancer cells through multiple signaling pathways: Evidence for involvement of transactivation of the epidermal growth factor receptor

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

Research output: Contribution to journalArticle

Abstract

Ovarian carcinoma cells release high amounts of endothelin-1 and exhibit increased expression of endothelin-A receptor. Engagement of the endothelin-A receptor triggers tumor growth, survival, neoangiogenesis and invasion. Cyclooxygenase-1 and cyclooxygenase-2 are enzymes involved in the production of prostaglandins and play a role in the regulation of tumor progression in several malignancies, including ovarian carcinomas. Endothelin-1 significantly increases the expression of cyclooxygenase-1 and cyclooxygenase-2 mRNA and protein, the activity of the cyclooxygenase-2 promoter, and the release of prostaglandin E2 from two ovarian carcinoma cell lines, HEY and OVCA 433. The cyclooxygenase-2 inhibitor, NS-398 drastically decreased the endothelin-1-induced prostaglandin E2 production and vascular endothelial growth factor upregulation, indicating a role for cyclooxygenase-2 in endothelin-1-induced vascular endothelial growth factor-mediated angiogenesis. In this study we demonstrated that endothelin-1-induced cyclooxygenase-2 and related prostaglandin E2 release were dependent upon the activation of endothelin-A receptor and of multiple mitogen-activated protein kinase signal pathways, including extracellular signal-regulated kinase 1/2 kinase, p38 mitogen-activated protein kinase and the transactivation of the epidermal growth factor receptor. In human ovarian xenografts, the levels of cyclooxygenase-2 protein expression were significantly reduced following treatment with the endothelin-A receptor selective antagonist, atrasentan, compared with untreated mice. These results suggest that the pharmacological blocking of endothelin-A receptor is an attractive strategy to control the cyclooxygenase-2 protein expression in ovarian carcinoma.

Original languageEnglish
JournalJournal of Cardiovascular Pharmacology
Volume44
Issue numberSUPPL. 1
DOIs
Publication statusPublished - Nov 2004

Keywords

  • COX-1
  • COX-2
  • Endothelin-1 (ET-1)
  • ET receptor
  • Ovarian carcinoma
  • PGE

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

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