Antagonists of growth hormone-releasing hormone inhibit growth of androgen-independent prostate cancer through inactivation of ERK and Akt kinases

Ferenc G. Rick, Andrew V. Schally, Luca Szalontay, Norman L. Block, Karoly Szepeshazi, Mehrdad Nadji, Marta Zarandi, Florian Hohla, Stefan Buchholz, Stephan Seitz

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

The management of castration-resistant prostate cancer (CRPC) presents a clinical challenge because of limitations in efficacy of current therapies. Novel therapeutic strategies for the treatment of CRPC are needed. Antagonists of hypothalamic growth hormone-releasing hormone (GHRH) inhibit growth of various malignancies, including androgen-dependent and independent prostate cancer, by suppressing diverse tumoral growth factors, especially GHRH itself, which acts as a potent autocrine/paracrine growth factor in many tumors.We evaluated the effects of the GHRH antagonist, JMR-132, on PC-3 human androgen-independent prostate cancer cells in vitro and in vivo. JMR-132 suppressed the proliferation of PC-3 cells in vitro in a dose-dependent manner and significantly inhibited growth of PC-3 tumors by 61% (P < 0.05). The expression of GHRH, GHRH receptors, and their main splice variant, SV1, in PC-3 cells and tumor xenografts was demonstrated by RT-PCR and Western blot. The content of GHRH protein in PC-3 xenografts was lowered markedly, by 66.3%(P < 0.01), after treatment with JMR-132. GHRH induced a significant increase in levels of ERK, but JMR-132 abolished this outcome. Our findings indicate that inhibition of PC-3 prostate cancer by JMR-132 involves inactivation of Akt and ERK. The inhibitory effect produced by GHRH antagonist can result in part from inactivation of the PI3K/Akt/mammalian target of rapamycin and Raf/MEK/ERK pathways and from the reduction in GHRH produced by cancer cells. Our findings support the role of GHRH as an autocrine growth factor in prostate cancer and suggest that antagonists of GHRH should be considered for further development as therapy for CRPC.

Original languageEnglish (US)
Pages (from-to)1655-1660
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number5
DOIs
StatePublished - Jan 31 2012

Keywords

  • Advanced prostate cancer
  • Hormone refractory prostate cancer
  • Novel treatment
  • Prostatic cell death
  • Targeted therapy

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Antagonists of growth hormone-releasing hormone inhibit growth of androgen-independent prostate cancer through inactivation of ERK and Akt kinases'. Together they form a unique fingerprint.

  • Cite this