GnRH-II agonist [D-Lys6]GnRH-II inhibits the EGF-induced mitogenic signal transduction in human endometrial and ovarian cancer cells.
The majority of human endometrial and ovarian cancers express receptors for GnRH type I (GnRH-I). Their proliferation is time- and dose-dependently reduced by GnRH-I and its analogs. GnRH-I analogs activate a phosphotyrosine-phosphatase (PTP) and inhibit EGF-induced mitogenic signal transduction. Recently we found that GnRH type II (GnRH-II) and its agonist [D-Lys6]GnRH-II also have antiproliferative effects on these tumor cells which are significantly greater than those of GnRH-I agonists. In a more recent study, we showed that the antiproliferative activity of GnRH-II on human endometrial and ovarian cancer cell lines is not mediated through the GnRH-I receptor. The underlying signal transduction mechanisms of GnRH-II are still unknown. In this study we showed that the mitogenic effects of growth factors in endometrial and ovarian cancer cell lines were counteracted by GnRH-II agonist [D-Lys6]GnRH-II, indicating an interaction with the mitogenic signal transduction. We showed that [D-Lys6]GnRH-II reduces EGF-induced auto-tyrosine-phosphorylation of EGF-receptors via activation of a PTP and that EGF-induced activation of mitogen-activated protein kinase was blocked in cells treated with [D-Lys6]GnRH-II. Furthermore, EGF-induced expression of the immediate early gene c-fos was inhibited by treatment with [D-Lys6]GnRH-II. After knock-out of GnRH-I receptor expression, GnRH-II agonist [D-Lys6]GnRH-II still activated PTP and inhibited the EGF-induced mitogenic signal transduction. These data indicate, that the effects of GnRH-II are not due to a cross-reaction with the GnRH-I receptor. In conclusion these data suggest that the signaling of GnRH-II agonist [D-Lys6]GnRH-II is comparable to that of GnRH-I analogs.
Eicke
Nicola
N
Department of Gynecology and Obstetrics, Georg-August University, D-37070 Göttingen, Germany.
Günthert
Andreas R
AR
Emons
Günter
G
Gründker
Carsten
C
D016889:Endometrial Neoplasms / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000819:agonists / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D010051:Ovarian Neoplasms / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D011966:Receptors, LHRH / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D017329:Triptorelin Pamoate / Q000494:pharmacology*
C484844:GNRHR protein, human; C427484:GNRHR2 protein, human; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D011966:Receptors, LHRH; D017329:Triptorelin Pamoate; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020930:MAP Kinase Kinase Kinases; D017027:Protein Tyrosine Phosphatases