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Inhibitory effects of antagonists of growth hormone releasing hormone on experimental prostate cancers are associated with upregulation of wild‐type p53 and decrease in p21 and mutant p53 proteins
Author(s) -
Stangelberger Anton,
Schally Andrew V.,
Rick Ferenc G.,
Varga Jozsef L.,
Baker Benjamin,
Zarandi Marta,
Halmos Gabor
Publication year - 2012
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.21458
Subject(s) - prostate cancer , antagonist , endocrinology , medicine , prostate , downregulation and upregulation , apoptosis , cancer research , biology , cell growth , receptor , cancer , gene , biochemistry , genetics
BACKGROUND The tumor suppressor gene p53 is implicated in cell cycle control and apoptosis. Antagonists of growth hormone‐releasing hormone (GHRH) have been shown to inhibit human experimental prostate cancers. METHODS We investigated the involvement of p53 apoptotic pathways in this effect. Nude mice bearing xenografted PC‐3, DU‐145, and MDA‐PCa‐2b human prostate cancer lines were treated with a new potent GHRH antagonist MZ‐J‐7‐138. To determine whether tumor inhibition by MZ‐J‐7‐138 involves apoptotic mechanisms such as p53 and p21, we evaluated by Western Blot the expression of mutant mt‐p53 in PC‐3 and DU‐145 and of wild type (wt‐p53) in MDA‐PCa‐2b prostate cancers as well as p21. RESULTS MZ‐J‐7‐138 significantly inhibited the growth of PC‐3, DU‐145, and MDA‐PCa‐2b xenografts in nude mice. Androgen deprivation with the LHRH antagonist Cetrorelix enhanced the anti‐proliferative effect of GHRH antagonist MZ‐J‐7‐138 on MDA‐PCa‐2b tumors. The expression of mutant (mt‐p53) and p21 protein in PC‐3 and DU‐145 tumors was significantly decreased by treatment with MZ‐J‐7‐138, whereas wild type wt‐p53 expression in MDA‐PCA‐2b tumors was up regulated by treatment with Cetrorelix. All three models investigated expressed specific, high affinity GHRH receptors. CONCLUSIONS Our findings indicate that the anti‐proliferative effects of GHRH antagonist MZ‐J‐7‐138 and LHRH antagonist Cetrorelix on prostate cancers involve p53 and p21 signaling. Prostate 72:555–565, 2012. © 2011 Wiley Periodicals, Inc.