Antagonist of Growth Hormone-Releasing Hormone Induces Apoptosis in LNCaP Human Prostate Cancer Cells through a Ca2+-Dependent Pathway

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2005-03, Vol.102 (9), p.3435-3440
Main Authors: Rekasi, Zoltan, Czompoly, Tamas, Schally, Andrew V., Boldizsar, Ferenc, Varga, Jozsef L., Zarandi, Marta, Berki, Timea, Horvath, Reka A., Nemeth, Peter
Format: Article
Language:English
Subjects:
Agonists
Annexins
Antagonist drugs
Apoptosis
Apoptosis - drug effects
Biological Sciences
Calcium
Calcium - metabolism
Cancer
Cell growth
Cell Line, Tumor
Cytometry
Edetic Acid - pharmacology
Flow Cytometry
Fluorescence
Growth Hormone-Releasing Hormone - analogs & derivatives
Growth Hormone-Releasing Hormone - antagonists & inhibitors
Growth Hormone-Releasing Hormone - pharmacology
Hormones
Humans
Male
Medical research
Nifedipine - pharmacology
Phosphatidylserines
Phosphatidylserines - metabolism
Prostate cancer
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Receptors
Signal transduction
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Summary: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) NH2inhibited 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0410006102