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This version published online on March 25, 2004
Molecular Endocrinology, doi:10.1210/me.2004-0022
Molecular Endocrinology Vol. 0, No. 2004 200400221-
doi:10.1210/me.2004-0022
Copyright © 2004 by the Endocrine Society.
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Submitted on January 19, 2004
Accepted on March 18, 2004

Elevated Prostaglandin EP2 Receptor in Endometrial Adenocarcinoma cells Promotes VEGF Expression via cAMP-mediated Transactivation of the EGF Receptor and ERK1/2 signaling pathways

Kurt J. Sales, Stuart Maudsley, and Henry N. Jabbour*

MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology. The University of Edinburgh Academic Center, 49 Little France Crescent, Old Dalkeith Road, Edinburgh, EH16 4SB, UK.

* To whom correspondence should be addressed. E-mail: h.jabbour{at}hrsu.mrc.ac.uk.

Prostaglandin (PG) E2 EP2 receptor is elevated in numerous carcinomas including the endometrium and has been implicated in mediating the effects of PGE2 on vascular function. In this study we investigated the intracellular signaling pathways that are activated by the EP2 receptor and their role in regulation of the expression of vascular endothelial growth factor (VEGF) in endometrial adenocarcinoma (Ishikawa) cells. Ishikawa cells were stably transfected with EP2 receptor cDNA in the sense or antisense directions. Treatment of Ishikawa cells with PGE2 rapidly induced transactivation of the epidermal growth factor receptor (EGFR) and activation of extracellular signal-regulated kinase (ERK1/2) via the EP2 receptor. Pre-incubation of cells with chemical inhibitors of protein kinase A, c-Src and EGFR kinase abolished the EP2-induced activation of EGFR and ERK1/2. PGE2 signaling via the EP2 receptor also promoted the mRNA expression and secretion of VEGF protein in Ishikawa cells. This effect was inhibited by pre-incubation with chemical inhibitors of EGFR kinase, ERK1/2 signaling, and small inhibitory RNA molecules (siRNA) targeted against the EGFR. Therefore we have demonstrated that elevated EP2 receptor expression may facilitate the PGE2-induced release of pro-angiogenic factors in reproductive tumor cells via intracellular cAMP-mediated transactivation of the EGFR and ERK1/2 pathways.
Key words: cyclooxygenase • prostaglandin E2 • EP2 receptor • EGFR transactivation • MAPK




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