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Seminal Plasma Promotes the Expression of Tumorigenic and Angiogenic Genes in Cervical Adenocarcinoma Cells via the E-Series Prostanoid 4 Receptor

Medical Research Council Human Reproductive Sciences Unit (M.M., K.J.S., H.N.J.), The Queen’s Medical Research Institute, Edinburgh EH16 4TJ, Scotland, United Kingdom; and Institute of Infectious Disease and Molecular Medicine (M.M., A.A.K.), Division of Medical Biochemistry, Faculty of Health Sciences, University of Cape Town, Cape Town, Rondebosch 7701, South Africa

Address all correspondence and requests for reprints to: Dr. Henry N. Jabbour, Medical Research Council Human Reproductive Sciences Unit, The Queen’s Institute for Medical Research, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, United Kingdom. E-mail: h.jabbour{at}hrsu.mrc.ac.uk.

E-series prostanoid (EP)4 receptor is up-regulated in numerous cancers, including cervical carcinomas, and has been implicated in mediating the effects of prostaglandin (PG)E₂ in tumorigenesis. In addition to regulation by endogenously biosynthesized PGE₂, neoplastic cervical epithelial cells in sexually active women may also be regulated by PGs present in seminal plasma. In this study, we investigated the signal transduction pathways mediating the role of seminal plasma and PGE₂ in the regulation of tumorigenic and angiogenic genes via the EP4 receptor in cervical adenocarcinoma (HeLa) cells. HeLa cells were stably transfected with EP4 receptor in the sense orientation. Seminal plasma and PGE₂ signaling via the EP4 receptor induced the activation of cyclooxygenase (COX)-2 and vascular endothelial growth factor (VEGF) promoters, expression of COX-2 and VEGF mRNA and protein, and secretion of VEGF protein into the culture medium. Treatment of HeLa cells with seminal plasma or PGE₂ also rapidly induced the phosphorylation of ERK1/2 via the EP4 receptor. Preincubation of cells with a specific EP4 receptor antagonist (ONO-AE2-227) or chemical inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase or MAPK kinase or cotransfection of cells with dominant-negative mutant cDNA targeted against the EGFR, serine/threonine kinase Raf, or MAPK kinase abolished the EP4-induced activation of COX-2, VEGF, and ERK1/2. Therefore, we have demonstrated that seminal plasma and PGE₂ can promote the expression of tumorigenic and angiogenic factors, in cervical adenocarcinoma cells via the EP4 receptor, EGFR, and ERK1/2 signaling pathways.