Endothelin-1-induced prostaglandin E3-EP2, EP4 signaling regulates vascular endothelial growth factor production and ovarian carcinoma cell invasion

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

Research output: Contribution to journalArticle

Abstract

Cycloosygenase (COX)-1- and COX-2-derived prostaglandins are implicated in the development and progression of several malignancies. We have recently demonstrated that treatment of ovarian carcinoma cells with endotkelin-1 (ET-1) induces expression of both COX-1 and COX-2, which contributes to vascular endothelial growth factor (VEGF) production. In this study, we show that in HEY and OVCA 433 ovarian carcinoma cells, ET-1, through the binding with ET A receptor (ET AR), induces prostaglandin E2 (PGE 2) production, as the more represented PG types, and increases the expression of PGE 2 receptor type 2 (EP2) and type 4 (EP4). The use of pharmacological EP agonists and antagonists indicates that ET-1 and PGE 2 stimulate VEGF production principally through EP2 and EP4 receptors. At the mechanistic level, we prove that the induction of PGE 2 and VEGF by ET-1 involves Src-mediated epidermal growth factor receptor transactivation. Finally, we demonstrate that ET AR-mediated activation of PGE 2-dependent signaling participates in the regulation of the invasive behavior of ovarian carcinoma cells by activating tumor-associated matrix metalloproteinase. These results implicate EP2 and EP4 receptors in the induction of VEGF expression and cell invasiveness by ET-1 and provide a mechanism by which. ET AR/ET-1 can promote and interact witli PGE 2-dependent machinery to amplify its proangiogenic and invasive phenotype in ovarian carcinoma cells. Pharmacological blockade of ET AR can therefore represent an additional strategy to control PGE 2 signaling, which has been associated with ovarian carcinoma progression.

Original languageEnglish
Pages (from-to)46700-46705
Number of pages6
JournalJournal of Biological Chemistry
Volume279
Issue number45
DOIs
Publication statusPublished - Nov 5 2004

ASJC Scopus subject areas

  • Biochemistry

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