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 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 microM) and induced early stage of apoptosis in LNCaP human prostate cancer cells at a concentration effective in suppression of cell proliferation (10 microM) 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 microM). 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 microM) 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.
Rekasi
Zoltan
Z
Department of Anatomy, University of Pécs, H-7624, Pécs, Hungary.
Czompoly
Tamas
T
Schally
Andrew V
AV
Boldizsar
Ferenc
F
Varga
Jozsef L
JL
Zarandi
Marta
M
Berki
Timea
T
Horvath
Reka A
RA
Nemeth
Peter
P
D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D004492:Edetic Acid / Q000494:pharmacology; D005434:Flow Cytometry; D013007:Growth Hormone-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009543:Nifedipine / Q000494:pharmacology; D010718:Phosphatidylserines / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology
C411623:JV 1-38; D010718:Phosphatidylserines; D013007:Growth Hormone-Releasing Hormone; D004492:Edetic Acid; D009543:Nifedipine; D002118:Calcium
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