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

Anton Stangelberger, Andrew V. Schally, Ferenc G. Rick, Jozsef L. Varga, Benjamin Baker, Marta Zarandi, Gabor Halmos

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)555-565
Number of pages11
JournalProstate
Volume72
Issue number5
DOIs
StatePublished - Apr 1 2012

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Keywords

  • androgen independent prostate cancer
  • apoptosis
  • GHRH antagonist
  • p21
  • p53

ASJC Scopus subject areas

  • Urology
  • Oncology

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