In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 10 ( 2009-05-15), p. 4202-4208
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 GADD45α 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 GADD45α 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 GADD45α with siRNA. Cells treated with GADD45α 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 GADD45α 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):4202–8]
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/0008-5472.CAN-08-4591
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2009
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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