Antagonist of growth hormone-releasing hormone induces apoptosis in LNCaP human prostate cancer cells through a Ca2+-dependent pathway

Zoltan Rekasi, Tamas Czompoly, Andrew V. Schally, Ferenc Boldizsar, Jozsef L. Varga, Marta Zarandi, Timea Berki, Reka A. Horvath, Peter Nemeth

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Antagonists of growth hormone-releasing hormone (GHRH) exert antiproliferative effects directly on cancer cells, which are mediated by the tumoral GHRH receptors. However, the signal transduction pathways involved in antiproliferative effect of GHRH antagonists have not yet been elucidated. We used flow cytometry to investigate whether GHRH antagonist JV-1-38 can induce changes in the cytosolic free Ca2+ concentration leading to apoptosis in LNCaP human prostate cancer cells. JV-1-38 evoked prompt Ca2+ signal in a dose-dependent way (1-10 μM) and induced early stage of apoptosis in LNCaP human prostate cancer cells at a concentration effective in suppression of cell proliferation (10 μM) peaking after 3 h. Unexpectedly, agonist GHRH(1-29)NH2, which elevates cytosolic free Ca2+ concentration in pituitary somatotrophs at nanomolar concentrations, failed to induce Ca2+ signal or apoptosis even at a 10-fold higher concentration (100 μM). However, agonist GHRH(1-29)NH2 inhibited JV-1-38-induced Ca2+ signals in a dose-dependent way without affecting the antagonist-induced apoptosis. Peptides unrelated to GHRH did not induce Ca2+ signals in LNCaP human prostate cancer cells. EDTA(10 mM) or nifedipine (10 μM) significantly reduced the Ca2+ signal and early stage of apoptosis induced by JV-1-38, supporting the view that the increase in intracellular Ca2+ in response to JV-1-38 occurs primarily through extracellular Ca2+ entry through voltage-operated Ca2+ channels. In conclusion, GHRH antagonists activate tumoral GHRH receptors and are able to induce apoptosis in LNCaP human prostate cancer cells through a Ca2+-dependent pathway. Treatment with GHRH antagonists may offer a new approach to the therapy of prostate and other hormone-sensitive cancers.

Original languageEnglish (US)
Pages (from-to)3435-3440
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number9
DOIs
StatePublished - Mar 1 2005
Externally publishedYes

Keywords

  • Calcium
  • Cancer therapy
  • Growth hormone-releasing hormone antagonist
  • Growth hormone-releasing hormone receptor

ASJC Scopus subject areas

  • Genetics
  • General

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