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Gonadotropin-releasing hormone type II induces apoptosis of human endometrial cancer cells by activating GADD45alpha.
MedLine Citation:
PMID:  19366794     Owner:  NLM     Status:  MEDLINE    
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 GADD45alpha 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 GADD45alpha 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 GADD45alpha with siRNA. Cells treated with GADD45alpha 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 GADD45alpha 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.
Hsien-Ming Wu; Jung-Chien Cheng; Hsin-Shih Wang; Hong-Yuan Huang; Colin D MacCalman; Peter C K Leung
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-04-14
Journal Detail:
Title:  Cancer research     Volume:  69     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2009 May 
Date Detail:
Created Date:  2009-05-18     Completed Date:  2009-07-08     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4202-8     Citation Subset:  IM    
Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada.
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MeSH Terms
Apoptosis / drug effects,  physiology*
Cell Division / drug effects
Cell Line, Tumor
Cell Survival / drug effects
Endometrial Neoplasms / enzymology,  genetics,  pathology*
Gonadotropin-Releasing Hormone / analogs & derivatives*,  pharmacology
Mitogen-Activated Protein Kinases / metabolism
RNA, Small Interfering / genetics
Receptors, LHRH / deficiency,  genetics,  physiology
p38 Mitogen-Activated Protein Kinases / metabolism
Reg. No./Substance:
0/GNRHR protein, human; 0/RNA, Small Interfering; 0/Receptors, LHRH; 33515-09-2/Gonadotropin-Releasing Hormone; 91097-16-4/LHRH, His(5)-Trp(7)-Tyr(8)-; EC Protein Kinases; EC Mitogen-Activated Protein Kinases

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