HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 45, 46700-46705, November 5, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/45/46700    most recent M408584200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Spinella, F. Articles by Bagnato, A. Search for Related Content PubMed PubMed Citation Articles by Spinella, F. Articles by Bagnato, A. Social Bookmarking                      What's this?

Endothelin-1-induced Prostaglandin E2-EP2, EP4 Signaling Regulates Vascular Endothelial Growth Factor Production and Ovarian Carcinoma Cell Invasion^*

Francesca Spinella, Laura Rosanò, Valeriana Di Castro, Pier Giorgio Natali¶, and Anna Bagnato||

From the Laboratories of Molecular Pathology and Ultrastructure and ^¶Immunology, Regina Elena Cancer Institute, 00158 Rome, Italy

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 ET_A receptor (ET_AR), 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 ET_AR-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 ET_AR/ET-1 can promote and interact with PGE₂-dependent machinery to amplify its proangiogenic and invasive phenotype in ovarian carcinoma cells. Pharmacological blockade of ET_AR can therefore represent an additional strategy to control PGE₂ signaling, which has been associated with ovarian carcinoma progression.

Received for publication, July 28, 2004 , and in revised form, September 2, 2004.

^* This work was supported by grants from the Associazione Italiana Ricerca sul Cancro, the Ministero della Salute, and from MIUR-Consiglio Nazionale delle Ricerche. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of fellowship from Fondazione Italiana Ricerca sul Cancro.

^|| To whom correspondence should be addressed: Laboratory of Molecular Pathology and Ultrastructure, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy. Tel.: 39-06-52662565; Fax: 39-06-52662505; E-mail: bagnato{at}ifo.it.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				T. Saeki, T. Ota, M. Aihara, and M. Araie Effects of Prostanoid EP Agonists on Mouse Intraocular Pressure Invest. Ophthalmol. Vis. Sci., May 1, 2009; 50(5): 2201 - 2208. [Abstract] [Full Text] [PDF]

				F. Spinella, E. Garrafa, V. Di Castro, L. Rosano, M. R. Nicotra, A. Caruso, P. G. Natali, and A. Bagnato Endothelin-1 Stimulates Lymphatic Endothelial Cells and Lymphatic Vessels to Grow and Invade Cancer Res., March 15, 2009; 69(6): 2669 - 2676. [Abstract] [Full Text] [PDF]

				C C Thorn, T C Freeman, N Scott, P J Guillou, and D G Jayne Laser microdissection expression profiling of marginal edges of colorectal tumours reveals evidence of increased lactate metabolism in the aggressive phenotype Gut, March 1, 2009; 58(3): 404 - 412. [Abstract] [Full Text] [PDF]

				J.-M. Oh, S.-H. Kim, Y.-I. Lee, M. Seo, S.-Y. Kim, Y.-S. Song, W.-H. Kim, and Y.-S. Juhnn Human papillomavirus E5 protein induces expression of the EP4 subtype of prostaglandin E2 receptor in cyclic AMP response element-dependent pathways in cervical cancer cells Carcinogenesis, January 1, 2009; 30(1): 141 - 149. [Abstract] [Full Text] [PDF]

				R. Hatazawa, A. Tanaka, M. Tanigami, K. Amagase, S. Kato, Y. Ashida, and K. Takeuchi Cyclooxygenase-2/prostaglandin E2 accelerates the healing of gastric ulcers via EP4 receptors Am J Physiol Gastrointest Liver Physiol, October 1, 2007; 293(4): G788 - G797. [Abstract] [Full Text] [PDF]

				L. Rosano, V. Di Castro, F. Spinella, G. Tortora, M. R. Nicotra, P. G. Natali, and A. Bagnato Combined Targeting of Endothelin A Receptor and Epidermal Growth Factor Receptor in Ovarian Cancer Shows Enhanced Antitumor Activity Cancer Res., July 1, 2007; 67(13): 6351 - 6359. [Abstract] [Full Text] [PDF]

				L. Rosano, V. Di Castro, F. Spinella, M. R. Nicotra, P. G. Natali, and A. Bagnato ZD4054, a specific antagonist of the endothelin A receptor, inhibits tumor growth and enhances paclitaxel activity in human ovarian carcinoma in vitro and in vivo Mol. Cancer Ther., July 1, 2007; 6(7): 2003 - 2011. [Abstract] [Full Text] [PDF]

				M J Grimshaw Endothelins and hypoxia-inducible factor in cancer Endocr. Relat. Cancer, June 1, 2007; 14(2): 233 - 244. [Abstract] [Full Text] [PDF]

				D. Ribatti, M. T. Conconi, and G. G. Nussdorfer Nonclassic Endogenous Novel Regulators of Angiogenesis Pharmacol. Rev., June 1, 2007; 59(2): 185 - 205. [Abstract] [Full Text] [PDF]

				F. Spinella, L. Rosano, V. Di Castro, S. Decandia, M. R. Nicotra, P. G. Natali, and A. Bagnato Endothelin-1 and Endothelin-3 Promote Invasive Behavior via Hypoxia-Inducible Factor-1{alpha} in Human Melanoma Cells Cancer Res., February 15, 2007; 67(4): 1725 - 1734. [Abstract] [Full Text] [PDF]

				L. Yang, Y. Huang, R. Porta, K. Yanagisawa, A. Gonzalez, E. Segi, D. H. Johnson, S. Narumiya, and D. P. Carbone Host and Direct Antitumor Effects and Profound Reduction in Tumor Metastasis with Selective EP4 Receptor Antagonism Cancer Res., October 1, 2006; 66(19): 9665 - 9672. [Abstract] [Full Text] [PDF]

				K. Wanggren, P.G. Lalitkumar, A. Stavreus-Evers, B. Stabi, and K. Gemzell-Danielsson Prostaglandin E2 and F2{alpha} receptors in the human Fallopian tube before and after mifepristone treatment Mol. Hum. Reprod., September 1, 2006; 12(9): 577 - 585. [Abstract] [Full Text] [PDF]

				F. Spinella, L. Rosano, S. Decandia, V. Di Castro, A. Albini, G. Elia, P. G. Natali, and A. Bagnato Antitumor Effect of Green Tea Polyphenol Epigallocatechin-3-Gallate in Ovarian Carcinoma Cells: Evidence for the Endothelin-1 as a Potential Target. Experimental Biology and Medicine, June 1, 2006; 231(6): 1123 - 1127. [Abstract] [Full Text] [PDF]

				F. Spinella, L. Rosano, V. Di Castro, S. Decandia, A. Albini, M. R. Nicotra, P. G. Natali, and A. Bagnato Green tea polyphenol epigallocatechin-3-gallate inhibits the endothelin axis and downstream signaling pathways in ovarian carcinoma. Mol. Cancer Ther., June 1, 2006; 5(6): 1483 - 1492. [Abstract] [Full Text] [PDF]

				D Wang and R N DuBois PROSTAGLANDINS AND CANCER Gut, January 1, 2006; 55(1): 115 - 122. [Full Text] [PDF]

				A. Bagnato, F. Spinella, and L. Rosano Emerging role of the endothelin axis in ovarian tumor progression Endocr. Relat. Cancer, December 1, 2005; 12(4): 761 - 772. [Abstract] [Full Text] [PDF]