Biology of the gonadotropin-releasing hormone system in gynecological cancers

Department of Gynecology and Obstetrics, Georg-August-University of Gottingen, Robert-Koch-Strasse 40, D-37070 Gottingen, Germany.

The expression of GnRH and its receptor as a part of an autocrine regulatory system of cell proliferation has been demonstrated in a number of human malignant tumors, including cancers of the breast, ovary and endometrium. Dose-dependent antiproliferative effects of GnRH agonists in cell lines derived from these cancers have been observed by various investigators. GnRH antagonists also have marked antiproliferative activity in most breast, ovarian and endometrial cancer cell lines tested, indicating that the dichotomy of GnRH agonists and antagonists might not apply to the GnRH system in cancer cells. The classical GnRH receptor signal-transduction mechanisms, known to operate in the pituitary, are not involved in the mediation of antiproliferative effects of GnRH analogs in cancer cells. Rather, the GnRH receptor interacts with the mitogenic signal transduction of growth factor receptors and related oncogene products associated with tyrosine kinase activity, via activation of a phosphotyrosine phosphatase, resulting in downregulation of cancer cell proliferation. In addition, GnRH activates nuclear factor kappaB and protects the cancer cells from apoptosis. Furthermore, GnRH induces activation of the c-Jun N-terminal kinase/activator protein-1 (AP-1) pathway independent of the known AP-1 activators, protein kinase or mitogen activated protein kinase.

This article has been cited by other articles:

				C. D. White, M. Coetsee, K. Morgan, C. A. Flanagan, R. P. Millar, and Z.-L. Lu A Crucial Role for G{alpha}q/11, But Not G{alpha}i/o or G{alpha}s, in Gonadotropin-Releasing Hormone Receptor-Mediated Cell Growth Inhibition Mol. Endocrinol., November 1, 2008; 22(11): 2520 - 2530. [Abstract] [Full Text] [PDF]

				R. Lopez de Maturana, A. J. Pawson, Z.-L. Lu, L. Davidson, S. Maudsley, K. Morgan, S. P. Langdon, and R. P. Millar Gonadotropin-Releasing Hormone Analog Structural Determinants of Selectivity for Inhibition of Cell Growth: Support for the Concept of Ligand-Induced Selective Signaling Mol. Endocrinol., July 1, 2008; 22(7): 1711 - 1722. [Abstract] [Full Text] [PDF]

				K. Walters, I. N. Wegorzewska, Y.-P. Chin, M. G. Parikh, and T. J. Wu Luteinizing Hormone-Releasing Hormone I (LHRH-I) and Its Metabolite in Peripheral Tissues Experimental Biology and Medicine, February 1, 2008; 233(2): 123 - 130. [Abstract] [Full Text] [PDF]

				C. Ferretti, L. Bruni, V. Dangles-Marie, A.P. Pecking, and D. Bellet Molecular circuits shared by placental and cancer cells, and their implications in the proliferative, invasive and migratory capacities of trophoblasts Hum. Reprod. Update, March 1, 2007; 13(2): 121 - 141. [Abstract] [Full Text] [PDF]

				S. Fister, A. R. Gunthert, G. Emons, and C. Grundker Gonadotropin-Releasing Hormone Type II Antagonists Induce Apoptotic Cell Death in Human Endometrial and Ovarian Cancer Cells In vitro and In vivo Cancer Res., February 15, 2007; 67(4): 1750 - 1756. [Abstract] [Full Text] [PDF]

				E. L. Baldwin, I. N. Wegorzewska, M. Flora, and T. J. Wu Regulation of Type II Luteinizing Hormone-Releasing Hormone (LHRH-II) Gene Expression by the Processed Peptide of LHRH-I, LHRH-(1-5) in Endometrial Cells Experimental Biology and Medicine, January 1, 2007; 232(1): 146 - 155. [Abstract] [Full Text] [PDF]

				N. Eicke, A. R Gunthert, V. Viereck, D. Siebold, M. Behe, T. Becker, G. Emons, and C. Grundker GnRH-II receptor-like antigenicity in human placenta and in cancers of the human reproductive organs Eur. J. Endocrinol., October 1, 2005; 153(4): 605 - 612. [Abstract] [Full Text] [PDF]

				A. R Gunthert, C. Grundker, A. Olota, J. Lasche, N. Eicke, and G. Emons Analogs of GnRH-I and GnRH-II inhibit epidermal growth factor-induced signal transduction and resensitize resistant human breast cancer cells to 4OH-tamoxifen Eur. J. Endocrinol., October 1, 2005; 153(4): 613 - 625. [Abstract] [Full Text] [PDF]

				K. Kawamura, J. Fukuda, J. Kumagai, Y. Shimizu, H. Kodama, A. Nakamura, and T. Tanaka Gonadotropin-Releasing Hormone I Analog Acts as an Antiapoptotic Factor in Mouse Blastocysts Endocrinology, September 1, 2005; 146(9): 4105 - 4116. [Abstract] [Full Text] [PDF]

				C. K. Cheng and P. C. K. Leung Molecular Biology of Gonadotropin-Releasing Hormone (GnRH)-I, GnRH-II, and Their Receptors in Humans Endocr. Rev., April 1, 2005; 26(2): 283 - 306. [Abstract] [Full Text] [PDF]

				W. Chen, S. Yoshida, N. Ohara, H. Matsuo, M. Morizane, and T. Maruo Gonadotropin-Releasing Hormone Antagonist Cetrorelix Down-Regulates Proliferating Cell Nuclear Antigen and Epidermal Growth Factor Expression and Up-Regulates Apoptosis in Association with Enhanced Poly(Adenosine 5'-Diphosphate-Ribose) Polymerase Expression in Cultured Human Leiomyoma Cells J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 884 - 892. [Abstract] [Full Text] [PDF]

				C. Grundker, A. Huschmand Nia, and G. Emons Gonadotropin-releasing hormone receptor-targeted gene therapy of gynecologic cancers Mol. Cancer Ther., February 1, 2005; 4(2): 225 - 232. [Abstract] [Full Text] [PDF]

				G S Harrison, M E Wierman, T M Nett, and L M Glode Gonadotropin-releasing hormone and its receptor in normal and malignant cells Endocr. Relat. Cancer, December 1, 2004; 11(4): 725 - 748. [Abstract] [Full Text] [PDF]

				S. Maudsley, L. Davidson, A. J. Pawson, R. Chan, R. L. de Maturana, and R. P. Millar Gonadotropin-Releasing Hormone (GnRH) Antagonists Promote Proapoptotic Signaling in Peripheral Reproductive Tumor Cells by Activating a G{alpha}i-Coupling State of the Type I GnRH Receptor Cancer Res., October 15, 2004; 64(20): 7533 - 7544. [Abstract] [Full Text] [PDF]

				N Angelopoulos, V Barbounis, S Livadas, D Kaltsas, and G Tolis Effects of estrogen deprivation due to breast cancer treatment Endocr. Relat. Cancer, September 1, 2004; 11(3): 523 - 535. [Abstract] [Full Text] [PDF]

				R. P. Millar and A. J. Pawson Outside-In and Inside-Out Signaling: The New Concept that Selectivity of Ligand Binding at the Gonadotropin-Releasing Hormone Receptor Is Modulated by the Intracellular Environment Endocrinology, August 1, 2004; 145(8): 3590 - 3593. [Full Text] [PDF]

				R. Auricchio, F. Paparo, M. Maglio, A. Franzese, F. Lombardi, G. Valerio, G. Nardone, S. Percopo, L. Greco, and R. Troncone In Vitro-Deranged Intestinal Immune Response to Gliadin in Type 1 Diabetes Diabetes, July 1, 2004; 53(7): 1680 - 1683. [Abstract] [Full Text] [PDF]

				A. Chamson-Reig, E. M. Sorianello, P. N. Catalano, M. O. Fernandez, O. P. Pignataro, C. Libertun, and V. A. R. Lux-Lantos Gonadotropin-Releasing Hormone Signaling Pathways in an Experimental Ovarian Tumor Endocrinology, July 1, 2003; 144(7): 2957 - 2966. [Abstract] [Full Text] [PDF]

				V. D. Dixit, H. Yang, V. Udhayakumar, and R. Sridaran Gonadotropin-Releasing Hormone Alters the T Helper Cytokine Balance in the Pregnant Rat Biol Reprod, June 1, 2003; 68(6): 2215 - 2221. [Abstract] [Full Text] [PDF]

				V. D. Dixit, R. Sridaran, M. A. Edmonsond, D. Taub, and W. E. Thompson Gonadotropin-Releasing Hormone Attenuates Pregnancy-Associated Thymic Involution and Modulates the Expression of Antiproliferative Gene Product Prohibitin Endocrinology, April 1, 2003; 144(4): 1496 - 1505. [Abstract] [Full Text] [PDF]

				C.-S. Chou, H. Zhu, E. Shalev, C. D. MacCalman, and P. C. K. Leung The Effects of Gonadotropin-Releasing Hormone (GnRH) I and GnRH II on the Urokinase-Type Plasminogen Activator/Plasminogen Activator Inhibitor System in Human Extravillous Cytotrophoblasts in Vitro J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5594 - 5603. [Abstract] [Full Text] [PDF]

				P. Morales, C. Pasten, and E. Pizarro Inhibition of In Vivo and In Vitro Fertilization in Rodents by Gonadotropin-Releasing Hormone Antagonists Biol Reprod, October 1, 2002; 67(4): 1360 - 1365. [Abstract] [Full Text] [PDF]