title: GnRH-II antagonists induce apoptosis in human endometrial, ovarian, and breast cancer cells via activation of stress-induced MAPKs p38 and JNK and proapoptotic protein Bax.
abstract: Recently, we could show that gonadotropin-releasing hormone (GnRH)-II antagonists induce apoptosis in human endometrial, ovarian, and breast cancer cells in vitro and in vivo. In the present study, we have ascertained receptor binding and effects of GnRH-II antagonists on mitogenic signal transduction and on activation of proapoptotic protein Bax. The GnRH-II antagonists tested showed EC50 values for GnRH-I receptor binding in the range of 1 to 2 nmol/L. The GnRH-II agonist [D-Lys6]GnRH-II showed an EC50 value for GnRH-I receptor binding of approximately 1,000 nmol/L. Agonistic activity on GnRH-I receptor function with an EC50 of 13 nmol/L has been determined for [D-Lys6]GnRH-II. Antagonistic activities with EC50 values in the range of 1 nmol/L were determined for the GnRH-II antagonists. Treatment of human endometrial, ovarian, and breast cancer cells with GnRH-II antagonists resulted in time-dependent activation of stress-induced mitogen-activated protein kinases p38 and c-Jun NH2-terminal kinase. In addition, treatment with GnRH-II antagonists induced time-dependent activation of proapoptotic protein Bax. GnRH-II antagonists are not involved in activation of protein kinase B/Akt or extracellular signal-regulated kinase 1/2. The GnRH-II antagonists tested had similar binding affinities to the GnRH-I receptor comparable with that of GnRH-I antagonist Cetrorelix. Referring to the cyclic AMP response element reporter gene activation assay, the GnRH-II agonist [D-Lys6]GnRH-II has to be classified as an agonist at the GnRH-I receptor, whereas the GnRH-II antagonists tested are clear antagonists at the GnRH-I receptor. GnRH-II antagonists induce apoptotic cell death in human endometrial, ovarian, and breast cancer cells via activation of stress-induced mitogen-activated protein kinases p38 and c-Jun NH2-terminal kinase followed by activation of proapoptotic protein Bax.
authors.affiliation: Department of Gynecology and Obstetrics, Georg-August-University, Göttingen, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Fister
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Günthert
authors.forename: Babette
authors.initials: B
authors.lastname: Aicher
authors.forename: Klaus W
authors.initials: KW
authors.lastname: Paulini
authors.forename: Günter
authors.initials: G
authors.lastname: Emons
authors.forename: Carsten
authors.initials: C
authors.lastname: Gründker
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000473:pathology*; D016889:Endometrial Neoplasms / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006727:Hormone Antagonists / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D010051:Ovarian Neoplasms / Q000473:pathology*; D011485:Protein Binding; D011966:Receptors, LHRH / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein / Q000378:metabolism / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology
chemical_list: D018931:Antineoplastic Agents, Hormonal; C484844:GNRHR protein, human; C543411:GnRH-II, Ac-2-Nal(1)-4Cpa(2)-3Pal(3,6)-Leu(8)-Ala(10)-; C505959:GnRH-II, Lys(6)-; D006727:Hormone Antagonists; D011966:Receptors, LHRH; D051028:bcl-2-Associated X Protein; D007987:Gonadotropin-Releasing Hormone; C047717:LHRH, His(5)-Trp(7)-Tyr(8)-; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases