Stimulation of neuroendocrine differentiation in prostate cancer cells by GHRH and its blockade by GHRH antagonists

被引:16
作者
Munoz-Moreno, Laura [1 ]
Carmena, Maria J. [1 ]
Schally, Andrew, V [2 ,3 ,4 ]
Prieto, Juan C. [1 ]
Bajo, Ana M. [1 ]
机构
[1] Univ Alcala, Dept Syst Biol, Alcala De Henares 28871, Spain
[2] Vet Affairs Med Ctr, Endocrine Polypeptide & Canc Inst, Miami, FL 33125 USA
[3] Univ Miami, Miller Sch Med, Dept Pathol & Med, Div Med Oncol, Miami, FL 33136 USA
[4] Univ Miami, Sylvester Comprehens Canc Ctr, Miller Sch Med, Miami, FL 33136 USA
关键词
GHRH; LNCaP cells; PC3; cells; Neuroendocrine differentiation; Exosomes; Prostate cancer; HORMONE-RELEASING-HORMONE; GROWTH; EXPRESSION; TRANSACTIVATION; MECHANISM; THERAPY; LINE; VIP;
D O I
10.1007/s10637-019-00831-2
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:746 / 754
页数:9
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