Luteinizing hormone-releasing hormone agonist triptorelin antagonizes signal transduction and mitogenic activity of epidermal growth factor in human ovarian and endometrial cancer cell lines

Günter Emons, Volker Müller, Olaf Ortmann, Gereon Grossmann, Ursula Trautner, Bettina V. Stuckrad, Klaus Dieter Schulz, Andrew V. Schally

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

This study was designed to elucidate the signal transduction mechanisms, mediating the antiproliferative effects of analogs of luteinizing hormone releasing hormone (LHRH) on cell lines derived from human cancers of the ovary (EFO-21, EFO-27) and the endometrium (HEC-1A, Ishikawa). The LHRH agonist triptorelin had no measurable effects on the activity of phospholipase C, protein kinase C, or adenylate cyclase in all 4 cell lines, though these enzymes could be activated through pharmacological stimuli. The proliferation of EFO-21, EFO-27 and HEC-1A cells in serum/phenol red-free medium was significantly stimulated by epidermal growth factor (EGF). This mitogenic effect of EGF was dose dependently antagonized by triptorelin, without affecting the concentrations of EGF receptors. Net tyrosine-phosphorylation induced by 1 nM EGF was nearly completely suppressed by simultaneous addition of 10 μM triptorelin or preincubation for 48 h with 100 nM triptorelin. This inhibitory effect of the LHRH agonist on EGF-induced net tyrosine phosphorylation was partly antagonized by exposure to 100 μM sodium vanadate, an inhibitor of phosphotyrosine phosphatase. In EFO-21, EFO-27, and HEC-1A cells exposure to 100 nM EGF for 5 min induced an approximately 5-fold increase in activity of mitogen activated protein kinase (MAP-kinase)/extracellular signal regulated kinase (ERK) which was virtually nullified, when the cells were exposed for 15 min to 10 μM triptorelin. These data suggest that LHRH signal transduction mechanisms based on the activation of phospholipase C, protein kinase C, and adenylate cyclase, which operate in the pituitary gonadotroph, are not necessarily involved in the mediation of the antiproliferative effects of triptorelin in these ovarian and endometrial cancer cell lines. Instead our findings support the hypothesis that triptorelin interferes with mitogenic signal transduction, probably through antagonizing tyrosine kinase activity of the EGF receptor.

Original languageEnglish (US)
Pages (from-to)1129-1137
Number of pages9
JournalInternational journal of oncology
Volume9
Issue number6
StatePublished - Dec 1 1996
Externally publishedYes

Keywords

  • endometrial cancer
  • gonadotropin releasing hormone
  • luteinizing hormone-releasing hormone
  • ovarian cancer
  • signal transduction

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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