title: Antagonist of growth hormone-releasing hormone induces apoptosis in LNCaP human prostate cancer cells through a Ca2+-dependent pathway.
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 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.
authors.affiliation: Department of Anatomy, University of Pécs, H-7624, Pécs, Hungary.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Rekasi
authors.forename: Tamas
authors.initials: T
authors.lastname: Czompoly
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.forename: Ferenc
authors.initials: F
authors.lastname: Boldizsar
authors.forename: Jozsef L
authors.initials: JL
authors.lastname: Varga
authors.forename: Marta
authors.initials: M
authors.lastname: Zarandi
authors.forename: Timea
authors.initials: T
authors.lastname: Berki
authors.forename: Reka A
authors.initials: RA
authors.lastname: Horvath
authors.forename: Peter
authors.initials: P
authors.lastname: Nemeth
mesh_terms: 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
chemical_list: C411623:JV 1-38; D010718:Phosphatidylserines; D013007:Growth Hormone-Releasing Hormone; D004492:Edetic Acid; D009543:Nifedipine; D002118:Calcium
references.citation: Endocrine. 2002 Jun;18(1):85-90
references.pmid: 12166629
references.citation: Endocrinology. 1991 Jan;128(1):592-603
references.pmid: 1670926
references.citation: Endocrinology. 2000 Jun;141(6):2120-8
references.pmid: 10830299
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14373-8
references.pmid: 9826707
references.citation: Lancet Oncol. 2002 May;3(5):298-302
references.pmid: 12067807
references.citation: Prostate. 2002 Aug 1;52(3):173-82
references.pmid: 12111694
references.citation: Breast Cancer Res Treat. 2000 Mar;60(1):71-9
references.pmid: 10845811
references.citation: Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8054-9
references.pmid: 12060752
references.citation: Proc Natl Acad Sci U S A. 1988 Mar;85(5):1637-41
references.pmid: 3278323
references.citation: Regul Pept. 2002 Oct 15;108(2-3):47-53
references.pmid: 12220726
references.citation: Peptides. 2002 Jun;23(6):1127-33
references.pmid: 12126741
references.citation: Peptides. 2002 Jun;23(6):1187-94
references.pmid: 12126750
references.citation: Immunol Lett. 2002 Jun 3;82(1-2):159-64
references.pmid: 12008048
references.citation: J Med Chem. 1976 Mar;19(3):423-5
references.pmid: 1255667
references.citation: Prostate. 2001 Oct 1;49(2):116-21
references.pmid: 11582590
references.citation: Breast Cancer Res Treat. 2003 Jan;77(1):15-26
references.pmid: 12602901
references.citation: Cancer. 2002 Oct 15;95(8):1735-45
references.pmid: 12365022
references.citation: Peptides. 2001 Jun;22(6):879-86
references.pmid: 11390017
references.citation: Front Neuroendocrinol. 2001 Oct;22(4):248-91
references.pmid: 11587553
references.citation: Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):196-200
references.pmid: 11773624
references.citation: Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11866-71
references.pmid: 12186980
references.citation: Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10561-6
references.pmid: 10962031
references.citation: Cell Mol Life Sci. 2004 May;61(9):1042-68
references.pmid: 15112052
references.citation: Mol Endocrinol. 1993 Jan;7(1):77-84
references.pmid: 7680413
references.citation: Expert Opin Investig Drugs. 2003 Aug;12(8):1385-94
references.pmid: 12882623
references.citation: Endocrinology. 2002 Apr;143(4):1475-84
references.pmid: 11897706
references.citation: Endocr Rev. 2000 Dec;21(6):619-70
references.pmid: 11133067
references.citation: Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15160-5
references.pmid: 15469915
references.citation: Biochem Biophys Res Commun. 1982 Nov 30;109(2):588-94
references.pmid: 6185122
references.citation: Endocrinology. 1995 Sep;136(9):4147-50
references.pmid: 7649123
references.citation: Ann N Y Acad Sci. 1996 Dec 26;805:184-203
references.pmid: 8993403
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9512-7
references.pmid: 12867592
references.citation: Trends Endocrinol Metab. 1999 Dec;10(10):383-391
references.pmid: 10542394
references.citation: Prostate. 2000 Oct 1;45(2):158-66
references.pmid: 11027415
references.citation: J Biol Chem. 1989 May 15;264(14):8171-8
references.pmid: 2498308
references.citation: Trends Endocrinol Metab. 2002 Sep;13(7):299-303
references.pmid: 12163232
references.citation: J Clin Endocrinol Metab. 2001 May;86(5):2144-52
references.pmid: 11344219
references.citation: Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10555-60
references.pmid: 10962030
references.citation: J Immunol Methods. 1995 Jul 17;184(1):39-51
references.pmid: 7622868
references.citation: Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14894-8
references.pmid: 10611309
references.citation: J Clin Endocrinol Metab. 2002 Oct;87(10):4707-14
references.pmid: 12364462
references.citation: Int J Cancer. 2004 Nov 20;112(4):570-6
references.pmid: 15382037
references.citation: Eur J Endocrinol. 2004 Sep;151(3):391-6
references.pmid: 15362970
references.citation: Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12298-302
references.pmid: 7991622
references.citation: Anticancer Drugs. 2001 Oct;12(9):761-8
references.pmid: 11593058
references.citation: Mol Endocrinol. 1992 Oct;6(10):1734-44
references.pmid: 1333056
references.citation: Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):532-4
references.pmid: 10639112
references.citation: Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):692-7
references.pmid: 9892695