Cellular mechanisms of growth inhibition of human epithelial ovarian cancer cell line by LH-releasing hormone antagonist Cetrorelix.

Abstract

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(-9) and 10(-5) 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(-5) 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(-5) 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(-5) 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.

• Authors: Xiaohui Tang, Tetsu Yano, Yutaka Osuga, Hirotaka Matsumi, Naomi Yano, Jiping Xu, Osamu Wada, Kaori Koga, Koji Kugu, Osamu Tsutsumi, Andrew V Schally, Yuji Taketani
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 87 Issue 8 Pg. 3721-7 (Aug 2002) ISSN: 0021-972X [Print] United States
• PMID: 12161501 (Publication Type: Journal Article)

Chemical References

• Hormone Antagonists
• RNA, Messenger
• Receptors, LHRH
• Gonadotropin-Releasing Hormone
• DNA
• cetrorelix

Topics

• Apoptosis (drug effects)
• Cell Division (drug effects)
• DNA (biosynthesis)
• Epithelial Cells (cytology, drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Genes, cdc (drug effects)
• Gonadotropin-Releasing Hormone (analogs & derivatives, antagonists & inhibitors, pharmacology)
• Hormone Antagonists (pharmacology)
• Humans
• Ovarian Neoplasms
• RNA, Messenger (analysis)
• Receptors, LHRH (genetics)
• Tumor Cells, Cultured (cytology, drug effects)