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Expression, Localization, and Signaling of Prostaglandin F₂ Receptor in Human Endometrial Adenocarcinoma: Regulation of Proliferation by Activation of the Epidermal Growth Factor Receptor and Mitogen-Activated Protein Kinase Signaling Pathways

Medical Research Council Human Reproductive Sciences Unit, Center for Reproductive Biology (K.J.S., R.A.A., H.N.J.), and Department of Pathology, University of Edinburgh Academic Center (A.R.W.W.), Edinburgh, United Kingdom EH16 4SB; and Fujisawa Institute of Neuroscience in Edinburgh, University of Edinburgh (S.A.M.), Edinburgh, United Kingdom EH8 9LE

Address all correspondence and requests for reprints to: Dr. Henry N. Jabbour, Medical Research Council Human Reproductive Sciences Unit, Center for Reproductive Biology, University of Edinburgh Academic Center, 49 Little France Crescent, Old Dalkeith Road, Edinburgh, United Kingdom EH16 4SB. E-mail: h.jabbour{at}hrsu.mrc.ac.uk.

Prostaglandin F₂(PGF₂) is a bioactive lipid biosynthesized by cyclooxygenase (COX) enzymes and mediates its biological activity via the heptahelical G_q-coupled PGF₂receptor (FP receptor). This study investigated the expression and molecular signaling of the FP receptor in human endometrial adenocarcinomas. Real-time RT-PCR and Western blot analysis confirmed FP receptor expression in endometrial adenocarcinoma of all grades and differentiation. The expression of FP receptor was up-regulated in all endometrial adenocarcinomas compared with normal endometrium. The site of FP receptor expression was localized by in situ hybridization and immunohistochemistry to the neoplastic epithelial cells in all adenocarcinomas. Treatment of endometrial adenocarcinoma explants with PGF₂ resulted in mobilization of inositol phosphate signaling, indicating functional FP receptor expression. We investigated whether PGF₂ could trans-activate the epidermal growth factor receptor (EGFR) and trigger the MAPK signaling pathway. Treatment of adenocarcinoma explants and endometrial adenocarcinoma cells (Ishikawa) with PGF₂-phosphorylated EGFR, triggered MAPK signaling and enhanced the proliferation of Ishikawa cells. Inactivation of phospholipase C, EGFR kinase, and MAPK kinase with specific inhibitors abolished PGF₂-induced trans-activation of EGFR, MAPK signaling, and Ishikawa cell proliferation. These data suggest that PGF₂-FP receptor promote endometrial tumorigenesis via a phospholipase C-mediated phosphorylation of the EGFR and MAPK signaling pathways.

Abbreviations: COX, Cyclooxygenase; d, deoxy; DMSO, dimethylsulfoxide; EGF, epidermal growth factor; EGFR, EGF receptor; FCS, fetal calf serum; FITC, fluorescein isothiocyanate; FP, GPCR for prostaglandin F₂; GPCR, G protein receptor; IP3, inositol trisphosphate; MEK, MAPK kinase; PGF₂, prostaglandin F₂; PLC, phospholipase C.

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