Cellular Mechanisms of Growth Inhibition of Human Epithelial Ovarian Cancer Cell Line by LH-Releasing Hormone Antagonist Cetrorelix
Xiaohui Tang,
Tetsu Yano,
Yutaka Osuga,
Hirotaka Matsumi,
Naomi Yano,
Jiping Xu,
Osamu Wada,
Kaori Koga,
Koji Kugu,
Osamu Tsutsumi,
Andrew V. Schally and
Yuji Taketani
Department of Obstetrics and Gynecology (X.T., T.Y., Y.O., H.M., N.Y., J.X., O.W., K.Ko., K.Ku., O.T., Y.T.), Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan; and Endocrine, Polypeptide and Cancer Institute (A.V.S.), Veterans Affairs Medical Center, and Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112
Address all correspondence and requests for reprints to: Dr. Tetsu Yano, Associate Professor, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, 7-3-1, Hongou, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: . tetu-tky{at}umin.ac.jp
Abstract
We investigated the direct effects of LH-releasing hormone (LH-RH)antagonist, Cetrorelix, on the growth of HTOA human epithelialovarian cancer cell line. RT-PCR revealed the expression ofmRNA for LH-RH and its receptor in HTOA cells. Cetrorelix, atconcentrations between 10-9 and10-5 M, exerted a dose-dependentantiproliferative action on HTOA cells, as measured by 5-bromo-2'-deoxyuridineincorporation into DNA. Flow cytometric analysis indicated thatCetrorelix, at 10-5 M, arrested cell cycle in HTOA cells, atG1 phase, after 24 h of treatment. Western blot analysis ofcell cycle-regulatory proteins demonstrated that treatment withCetrorelix (10-5 M) for 24 h did not change the steady-statelevels of cyclin D1, cyclin E, and cyclin-dependent kinase (Cdk)4but decreased the levels of cyclin A and Cdk2. The protein levelsof p21 (a Cdk inhibitor) and p53 (a suppressor of tumor cellgrowth and a positive regulator for p21 expression) were increasedby Cetrorelix, but the levels of p27 (a Cdk inhibitor) did notchange significantly. Flow cytometric analysis and terminaldeoxynucleotidyltransferase-mediated deoxyuridine 5-triphosphatenick end labeling staining demonstrated that Cetrorelix (10-5M) induced apoptosis in HTOA cells. In conclusion, Cetrorelixdirectly inhibits the proliferation of human epithelial ovariancancer cells through mechanisms mediated by LH-RH receptor andinvolving multiple events in cell cycle progression, includingG1 phase cell cycle arrest coupled with down-regulation of cyclinA-Cdk2 complex levels, presumably attributable to an up-regulationof p53 and p21 protein levels and apoptosis.
This article has been cited by other articles:
P. C.K. Leung and J.-H. Choi Endocrine signaling in ovarian surface epithelium and cancer
Hum. Reprod. Update,
March 1, 2007;
13(2):
143 - 162.
[Abstract][Full Text][PDF]
M. Bilotas, R.I. Baranao, R. Buquet, C. Sueldo, M. Tesone, and G. Meresman Effect of GnRH analogues on apoptosis and expression of Bcl-2, Bax, Fas and FasL proteins in endometrial epithelial cell cultures from patients with endometriosis and controls
Hum. Reprod.,
March 1, 2007;
22(3):
644 - 653.
[Abstract][Full Text][PDF]
Y. Hirota, Y. Osuga, K. Koga, O. Yoshino, T. Hirata, C. Morimoto, M. Harada, Y. Takemura, E. Nose, T. Yano, et al. The Expression and Possible Roles of Chemokine CXCL11 and Its Receptor CXCR3 in the Human Endometrium
J. Immunol.,
December 15, 2006;
177(12):
8813 - 8821.
[Abstract][Full Text][PDF]
J.-H. Choi, K.-C. Choi, N. Auersperg, and P. C K Leung Differential regulation of two forms of gonadotropin-releasing hormone messenger ribonucleic acid by gonadotropins in human immortalized ovarian surface epithelium and ovarian cancer cells.
Endocr. Relat. Cancer,
June 1, 2006;
13(2):
641 - 651.
[Abstract][Full Text][PDF]
Y. Hirota, Y. Osuga, T. Hirata, M. Harada, C. Morimoto, O. Yoshino, K. Koga, T. Yano, O. Tsutsumi, and Y. Taketani Activation of protease-activated receptor 2 stimulates proliferation and interleukin (IL)-6 and IL-8 secretion of endometriotic stromal cells
Hum. Reprod.,
December 1, 2005;
20(12):
3547 - 3553.
[Abstract][Full Text][PDF]
C. Morimoto, Y. Osuga, T. Yano, Y. Takemura, M. Harada, T. Hirata, Y. Hirota, O. Yoshino, K. Koga, K. Kugu, et al. GnRH II as a possible cytostatic regulator in the development of endometriosis
Hum. Reprod.,
November 1, 2005;
20(11):
3212 - 3218.
[Abstract][Full Text][PDF]
K. Maiti, D. Y. Oh, J. S. Moon, S. Acharjee, J. H. Li, D. G. Bai, H.-S. Park, K. Lee, Y. C. Lee, N. C. Jung, et al. Differential Effects of Gonadotropin-Releasing Hormone (GnRH)-I and GnRH-II on Prostate Cancer Cell Signaling and Death
J. Clin. Endocrinol. Metab.,
July 1, 2005;
90(7):
4287 - 4298.
[Abstract][Full Text][PDF]
Y. Hirota, Y. Osuga, T. Hirata, O. Yoshino, K. Koga, M. Harada, C. Morimoto, E. Nose, T. Yano, O. Tsutsumi, et al. Possible Involvement of Thrombin/Protease-Activated Receptor 1 System in the Pathogenesis of Endometriosis
J. Clin. Endocrinol. Metab.,
June 1, 2005;
90(6):
3673 - 3679.
[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]
Y. Hirota, Y. Osuga, K. Koga, O. Yoshino, T. Hirata, M. Harada, C. Morimoto, T. Yano, O. Tsutsumi, S. Sakuma, et al. Possible implication of midkine in the development of endometriosis
Hum. Reprod.,
April 1, 2005;
20(4):
1084 - 1089.
[Abstract][Full Text][PDF]
Y. Hirota, Y. Osuga, T. Hirata, K. Koga, O. Yoshino, M. Harada, C. Morimoto, E. Nose, T. Yano, O. Tsutsumi, et al. Evidence for the Presence of Protease-Activated Receptor 2 and Its Possible Implication in Remodeling of Human Endometrium
J. Clin. Endocrinol. Metab.,
March 1, 2005;
90(3):
1662 - 1669.
[Abstract][Full Text][PDF]
R. Guillemin Hypothalamic hormones a.k.a. hypothalamic releasing factors
J. Endocrinol.,
January 1, 2005;
184(1):
11 - 28.
[Abstract][Full Text][PDF]
