Stimulation of neuroendocrine differentiation in prostate cancer cells by GHRH and its blockade by GHRH antagonists.
Authors
Muñoz Moreno, Laura; Carmena Sierra, María José; Schally, Andrew V; Prieto, Juan C.; Bajo Chueca, Ana MaríaIdentifiers
Permanent link (URI): http://hdl.handle.net/10017/59345DOI: 10.1007/s10637-019-00831-2
ISSN: 0167-6997
Date
2020-07Funders
Universidad de Alcalá
Bibliographic citation
Investigational New Drugs, 2020, v. 38, n. 3, p. 746-754
Keywords
GHRH
LNCaP cells
PC3 cells
Neuroendocrine differentiation
Exosomes
Prostate cancer
Project
info:eu-repo/grantAgreement/UAH//CCG2015%2FBIO-010/ES/
info:eu-repo/grantAgreement/UAH//CCG2014%2FBIO-028/ES/
Document type
info:eu-repo/semantics/article
Version
info:eu-repo/semantics/aceptedVersion
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
© Springer
Access rights
info:eu-repo/semantics/openAccess
Abstract
Prostate cancer is the second leading cause of cancer-related deaths among men in developed countries. Neuroendocrine prostate cancer, in particular, is associated with an aggressive phenotype and a poor prognosis. Neuroendocrine cells produce and secrete peptide hormones and growth factors in a paracrine/autocrine manner which promote the progression of the disease. Recent studies have demonstrated that extracellular vesicles or exosomes are released by prostate cancer cells, supporting the spread of prostate cancer. Hence, the aim of this study was to investigate the effect of growth hormone-releasing hormone (GHRH) on neuroendocrine differentiation (NED) in the androgen-dependent prostate cancer cell line LNCaP and the molecular mechanisms underlying these effects. GHRH induced an increase in the percentage of neurite-bearing cells and in the protein levels of Neuron-Specific Enolase. Both effects were blocked by the GHRH receptor antagonist MIA-690. In addition, pretreatment of these cells with the calcium chelator BAPTA, the EGFR inhibitor AG-1478 or the HER2 inhibitor AG-825 reduced the effect of GHRH, suggesting that the GHRH-induced stimulation of NED involves calcium channel activation and EGFR/HER2 transactivation. Finally, PC3-derived exosomes led to an increase in NED, cell proliferation and cell adhesion. Altogether, these findings suggest that GHRH antagonists should be considered for in the management of neuroendocrine prostate cancer.
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