|
Title
|
|
|
|
Gonadotropin-releasing hormone (GnRH) antagonists promote proapoptotic signaling in peripheral reproductive tumor cells by activating a -coupling state of the type I GnRH receptor
|
|
|
Author
|
|
|
|
|
|
|
Abstract
|
|
|
|
| Gonadotropin-releasing hormone (GnRH) receptor agonists are extensively used in the treatment of sex hormone-dependent cancers via the desensitization of pituitary gonadotropes and consequent decrease in steroid sex hormone secretion. However, evidence now points to a direct inhibitory effect of GnRH analogs on cancer cells. These effects appear to be mediated via the Galpha(1)-type G protein, in contrast to the predominant Galpha(q) coupling in gonadotropes. Unlike Galpha(q) coupling, Galpha(i) coupling of the GnRH receptor can be activated by both agonists and antagonists. This unusual pharmacology suggested that the receptor involved in the cancer cells may not be the classical gonadotrope type I GnRH receptor. However, we have previously shown that a functional type 11 GnRH receptor is not present in man. In the present study, we show that GnRH agonists and selective GnRH antagonists exert potent antiproliferative effects on JEG-3 choriocarcinoma, benign prostate hyperplasia (BPH-1), and HEK293 cells stably expressing the type I GnRH receptor. This antiproliferative action occurs through a Galpha(i)-mediated activation of stress-activated protein kinase pathways, resulting in caspase activation and transmembrane transfer of phosphatidlyserine to the outer membrane envelope. Structurally related antagonistic GnRH analogs displayed divergent antiproliferative efficacies but demonstrated equal efficacies in inhibiting GnRH-induced Galpha(i)-based signaling. Therefore the ability of GnRH receptor antagonists to exert an antiproliferative effect on reproductive tumors may be dependent on ligand-selective activation of the Galpha(i)-coupled form of the type I GnRH receptor. |
|
|
|
Language
|
|
|
|
English
|
|
|
Source (journal)
|
|
|
|
Cancer research. - Baltimore, Md, 1941, currens
|
|
|
Publication
|
|
|
|
Baltimore, Md
:
Waverly
,
2004
|
|
|
ISSN
|
|
|
|
0008-5472
[print]
1538-7445
[online]
|
|
|
DOI
|
|
|
|
10.1158/0008-5472.CAN-04-1360
|
|
|
Volume/pages
|
|
|
|
64
:20
(2004)
, p. 7533-7544
|
|
|
ISI
|
|
|
|
000224522200051
|
|
|
Full text (Publisher's DOI)
|
|
|
|
|
|
|
Full text (publisher's version - intranet only)
|
|
|
|
|
|