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Cell and Tumor Biology |
-FP Receptor Interaction in Human Endometrial Adenocarcinomas
1 Medical Research Council Human Reproductive Sciences Unit, Centre for Reproductive Biology and 2 Department of Pathology, University of Edinburgh, Edinburgh, United Kingdom and 3 Department of Biochemistry, Tel Aviv University, Ramat Aviv, Israel
Requests for reprints: Henry N. Jabbour, Medical Research Council Human Reproductive Sciences Unit, Centre for Reproductive Biology, University of Edinburgh Academic Center, 49 Little France Crescent, Old Dalkeith Road, Edinburgh EH16 4SB, United Kingdom. Phone: 44-131-2426220; Fax: 44-131-2426231; E-mail: h.jabbour{at}hrsu.mrc.ac.uk.
Prostaglandins have been implicated in several neovascular diseases. In the present study, we found elevated FP receptor and vascular endothelial growth factor (VEGF) expression colocalized in glandular epithelial and vascular cells lining the blood vessels in endometrial adenocarcinomas. We investigated the signaling pathways activated by the FP receptor and their role in modulating VEGF expression in endometrial adenocarcinoma (Ishikawa) cells. Ishikawa cells were stably transfected with FP receptor cDNA in the sense or antisense orientations. Treatment of Ishikawa cells with prostaglandin F2
(PGF2) rapidly induced transphosphorylation of the epidermal growth factor receptor (EGFR) and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 via the FP receptor. Activation of EGFR-Ras-mitogen-activated protein kinase/ERK kinase (MEK) signaling via the FP receptor resulted in an increase in VEGF promoter activity, expression of VEGF mRNA, and secretion of VEGF protein. These effects of PGF2 on the FP receptor could be abolished by treatment of cells with a specific FP receptor antagonist, chemical inhibitors of c-Src, matrix metalloproteinase, and EGFR kinase or by inactivation of signaling with dominant-negative mutant isoforms of EGFR, Ras, or MEK or with small inhibitory RNA oligonucleotides targeted against the EGFR. Finally, we confirmed that PGF2 could potentiate angiogenesis in endometrial adenocarcinoma explants by transactivation of the EGFR and induction of VEGF mRNA expression.
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