Direct effects of luteinizing hormone-releasing hormone agonists and antagonists on MCF-7 mammary cancer cells

T. Segal-Abramson, H. Kitroser, J. Levy, A. V. Schally, Y. Sharoni

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

The binding of luteinizing hormone-releasing hormone (LH-RH) analogues to the human mammary tumor cell line MCF-7 and their effect on the cell proliferation was studied to elucidate their direct action on estrogen-dependent mammary tumors. The growth rate of these cells was doubled by the addition of 1 nM estradiol to cells maintained in an estrogen-deflcient medium. Although the basal growth rate was only slightly inhibited by the LH-RH antagonist [Ac-D-Nal(2)1,D-Phe(pCl)2,D-Pal(3)3,D-Cit 6,D-Ala10]LH-RH (SB-75), the estrogen-stimulated growth was completely abolished by the antagonist. In contrast, the LH-RH agonist buserelin stimulated cell growth in estrogen-deficient medium, whereas it had no effect in the presence of estrogen. 125I-labeled buserelin was used for the measurement of LH-RH receptors on MCF-7 cells. A Scatchard plot analysis of buserelin-specific binding revealed a nonlinear plot, which suggested the presence of one high-affinity binding site with a Kd of 1.4 ± 1.0 nM and the remaining sites with low affinity (Kd = 1.3 ± 1.0 μM). The binding of 125I-labeled buserelin was displaced equally well by unlabeled buserelin and by the LH-RH antagonist SB-75, suggesting that both analogues are bound to the same receptor. When parallel experiments were performed with 125I-labeled SB-75, the binding was displaced by unlabeled SB-75 and other antagonists, but only partially displaced by unlabeled buserelin. The results suggest that in these mammary tumor cells there is a LH-RH antagonist binding site that is not recognizable by LH-RH agonists. This hypothesis was tested by measuring cell growth in the presence of both agonists and antagonists. It was found that SB-75 inhibited the stimulation of growth by buserelin, but buserelin did not prevent the inhibition by the antagonist of the estrogen-dependent growth. These results suggest that antagonists directly inhibit mammary tumor growth, not only by competing with LH-RH high-affinity receptors, but also by other mechanisms mediated by low-affinity antagonist binding sites.

Original languageEnglish (US)
Pages (from-to)2336-2339
Number of pages4
JournalProceedings of the National Academy of Sciences of the United States of America
Volume89
Issue number6
DOIs
StatePublished - Jan 1 1992
Externally publishedYes

Keywords

  • Cell growth
  • Luteinizing hormone-releasing hormone analogues
  • Receptors

ASJC Scopus subject areas

  • Genetics
  • General

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