title: Endothelin-1-induced prostaglandin E2-EP2, EP4 signaling regulates vascular endothelial growth factor production and ovarian carcinoma cell invasion.
abstract: Cyclooxygenase (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 endothelin-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 ETA receptor (ETAR), induces prostaglandin E2 (PGE2) production, as the more represented PG types, and increases the expression of PGE2 receptor type 2 (EP2) and type 4 (EP4). The use of pharmacological EP agonists and antagonists indicates that ET-1 and PGE2 stimulate VEGF production principally through EP2 and EP4 receptors. At the mechanistic level, we prove that the induction of PGE2 and VEGF by ET-1 involves Src-mediated epidermal growth factor receptor transactivation. Finally, we demonstrate that ETAR-mediated activation of PGE2-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 ETAR/ET-1 can promote and interact with PGE2-dependent machinery to amplify its proangiogenic and invasive phenotype in ovarian carcinoma cells. Pharmacological blockade of ETAR can therefore represent an additional strategy to control PGE2 signaling, which has been associated with ovarian carcinoma progression.
authors.affiliation: Laboratories of Molecular Pathology and Ultrastructure and Immunology, Regina Elena Cancer Institute, 00158 Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Spinella
authors.forename: Laura
authors.initials: L
authors.lastname: Rosanò
authors.forename: Valeriana
authors.initials: V
authors.lastname: Di Castro
authors.forename: Pier Giorgio
authors.initials: PG
authors.lastname: Natali
authors.forename: Anna
authors.initials: A
authors.lastname: Bagnato
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D015232:Dinoprostone / Q000378:metabolism*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015533:Transcriptional Activation; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D019332:Endothelin-1; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D042461:Vascular Endothelial Growth Factor A; D019061:src-Family Kinases; D015232:Dinoprostone