Gonadotropin-Releasing Hormone Type II Induces Apoptosis of Human Endometrial Cancer Cells by Activating GADD45

¹Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada; ²Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center; and ³Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan, R.O.C.

^* To whom correspondence should be addressed. E-mail: peleung{at}interchange.ubc.ca.

	Abstract

Gonadotropin-releasing hormone type II (GnRH-II) has an antiproliferative effect on human endometrial cancer cells. Apoptosis in cancer cells may play a critical role in regulating cell proliferation. However, more studies are necessary to elucidate the underlying molecular mechanisms and develop potential applications of GnRH-II. Therefore, we explored the mechanisms of GnRH-II–induced apoptosis and the effects of GnRH-II on GADD45 activation in human endometrial cancer cell lines. GnRH-II decreased cell viability in a dose- and time-dependent manner. Apoptosis was induced with increased terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling apoptotic cells after GnRH-II treatment. Knockdown of the endogenous GnRH-I receptor with small interfering RNA (siRNA) rescued the cells from GnRH-II–mediated cell growth inhibition and abolished the induction of apoptosis. GnRH-II activated extracellular signal–regulated kinase (ERK)-1/2 and p38 mitogen-activated protein kinase (MAPK) in a time-dependent manner, and the activation was abolished by GnRH-I receptor siRNA and MAPK inhibitors. Cells pretreated with MAPK inhibitors were rescued from GnRH-II–mediated cell growth inhibition. Moreover, both inhibitors abolished GnRH-II–induced apoptosis. GnRH-II induced GADD45 expression, which was abolished by knockdown of endogenous GnRH-I receptors and MAPK inhibitors. GnRH-II–stimulated cell growth inhibition was rescued by knockdown of endogenous GADD45 with siRNA. Cells treated with GADD45 siRNA were refractory to GnRH-II–induced apoptosis. Thus, GnRH-II inhibits cell growth by inducing apoptosis through binding of the GnRH-I receptor, activation of the ERK1/2 and p38 MAPK pathways, and induction of GADD45 signaling. This finding may provide a new concept relating to the mechanism of GnRH-II–induced antiproliferation and apoptosis in endometrial cancer cells, indicating the possibility of GnRH-II as a promising therapeutic intervention for human endometrial cancer. [Cancer Res 2009;69(10): OF1–7]

Key Words: Gonadotropin-Releasing Hormone, Apoptosis, GADD45