Cellular Mechanisms of Growth Inhibition of Human Epithelial Ovarian Cancer Cell Line by LH-Releasing Hormone Antagonist Cetrorelix

• Published in: The journal of clinical endocrinology and metabolism Vol. 87; no. 8; pp. 3721 - 3727
• Main Authors: Tang, Xiaohui, Yano, Tetsu, Osuga, Yutaka, Matsumi, Hirotaka, Yano, Naomi, Xu, Jiping, Wada, Osamu, Koga, Kaori, Kugu, Koji, Tsutsumi, Osamu, Schally, Andrew V, Taketani, Yuji
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Copyright by The Endocrine Society 01.08.2002; Endocrine Society
• Subjects: Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Cell Division - drug effects; Chemotherapy; DNA - biosynthesis; Epithelial Cells - cytology; Epithelial Cells - drug effects; Female; Gene Expression Regulation, Neoplastic - drug effects; Genes, cdc - drug effects; Gonadotropin-Releasing Hormone - analogs & derivatives; Gonadotropin-Releasing Hormone - antagonists & inhibitors; Gonadotropin-Releasing Hormone - pharmacology; Hormone Antagonists - pharmacology; Humans; Medical sciences; Ovarian Neoplasms; Pharmacology. Drug treatments; Receptors, LHRH - genetics; RNA, Messenger - analysis; Tumor Cells, Cultured - cytology; Tumor Cells, Cultured - drug effects; Antineoplastic agent; Human; Cell proliferation; Cell culture; Decapeptide; Peptides; Gonadotropin RH; Malignant tumor; In vitro; Biological activity; Female genital diseases; Ovarian diseases; Ovary; G1 Phase; Cell cycle; Antagonist; Cetrorelix; Apoptosis
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.87.8.3721

We investigated the direct effects of LH-releasing hormone (LH-RH) antagonist, Cetrorelix, on the growth of HTOA human epithelial ovarian cancer cell line. RT-PCR revealed the expression of mRNA for LH-RH and its receptor in HTOA cells. Cetrorelix, at concentrations between 10 and10 m, exerted a dose-dependent antiproliferative action on HTOA cells, as measured by 5-bromo-2′-deoxyuridine incorporation into DNA. Flow cytometric analysis indicated that Cetrorelix, at 10 m, arrested cell cycle in HTOA cells, at G1 phase, after 24 h of treatment. Western blot analysis of cell cycle-regulatory proteins demonstrated that treatment with Cetrorelix (10 m) for 24 h did not change the steady-state levels of cyclin D1, cyclin E, and cyclin-dependent kinase (Cdk)4 but decreased the levels of cyclin A and Cdk2. The protein levels of p21 (a Cdk inhibitor) and p53 (a suppressor of tumor cell growth and a positive regulator for p21 expression) were increased by Cetrorelix, but the levels of p27 (a Cdk inhibitor) did not change significantly. Flow cytometric analysis and terminal deoxynucleotidyltransferase-mediated deoxyuridine 5-triphosphate nick end labeling staining demonstrated that Cetrorelix (10 m) induced apoptosis in HTOA cells. In conclusion, Cetrorelix directly inhibits the proliferation of human epithelial ovarian cancer cells through mechanisms mediated by LH-RH receptor and involving multiple events in cell cycle progression, including G1 phase cell cycle arrest coupled with down-regulation of cyclin A-Cdk2 complex levels, presumably attributable to an up-regulation of p53 and p21 protein levels and apoptosis.