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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

¹ Department of Gynecology and Obstetrics, Georg-August-University, Göttingen, Germany and ² Drug Discovery and Preclinical Development, Æterna Zentaris GmbH, Frankfurt, Germany

Requests for reprints: Carsten Gründker, Department of Gynecology and Obstetrics, Georg-August-University, Robert-Koch-Street 40, 37075 Göttingen, Germany. Phone: 49-551-399810; Fax: 49-551-399811; E-mail: grundker{at}med.uni-goettingen.de.

Key Words: GnRH-II antagonists • apoptosis • p38 • JNK • Bax

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 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. [Cancer Res 2009;69(16):6473–81]