GnRH-II agonist [D-Lys6]GnRH-II inhibits the EGF-induced mitogenic signal transduction in human endometrial and ovarian cancer cells

Int J Oncol. 2006 Nov;29(5):1223-9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Endometrial Neoplasms / metabolism*
  • Epidermal Growth Factor / antagonists & inhibitors
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / agonists
  • ErbB Receptors / antagonists & inhibitors*
  • Female
  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • Ovarian Neoplasms / metabolism*
  • Protein Tyrosine Phosphatases / drug effects
  • Proto-Oncogene Proteins c-fos / agonists
  • Proto-Oncogene Proteins c-fos / antagonists & inhibitors
  • Proto-Oncogene Proteins c-fos / genetics
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism
  • Receptors, LHRH / agonists*
  • Receptors, LHRH / antagonists & inhibitors
  • Receptors, LHRH / genetics
  • Signal Transduction / drug effects
  • Triptorelin Pamoate / pharmacology*


  • GNRHR protein, human
  • GNRHR2 protein, human
  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Receptors, LHRH
  • Triptorelin Pamoate
  • Epidermal Growth Factor
  • ErbB Receptors
  • MAP Kinase Kinase Kinases
  • Protein Tyrosine Phosphatases