Department of Systems Biology, University of Alcalá, 28871, Alcalá de Henares, Spain.
Veterans Affairs Medical Center, Endocrine, Polypeptide and Cancer Institute, Miami, FL, 33125, USA.
Invest New Drugs. 2020 Jun;38(3):746-754. doi: 10.1007/s10637-019-00831-2. Epub 2019 Jul 17.
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.
在发达国家，前列腺癌是男性癌症相关死亡的第二大主要原因。特别是神经内分泌前列腺癌与侵袭性表型和预后不良相关。神经内分泌细胞以旁分泌/自分泌的方式产生和分泌肽激素和生长因子，促进疾病的进展。最近的研究表明，前列腺癌细胞释放细胞外囊泡或外泌体，支持前列腺癌的扩散。因此，本研究旨在探讨生长激素释放激素（GHRH）对雄激素依赖性前列腺癌细胞系 LNCaP 中神经内分泌分化（NED）的影响及其分子机制。GHRH 诱导具有神经突的细胞百分比和神经元特异性烯醇化酶蛋白水平增加。这两种作用均被 GHRH 受体拮抗剂 MIA-690 阻断。此外，用钙螯合剂 BAPTA、EGFR 抑制剂 AG-1478 或 HER2 抑制剂 AG-825 预处理这些细胞，可降低 GHRH 的作用，表明 GHRH 诱导的 NED 刺激涉及钙通道激活和 EGFR/HER2 反式激活。最后，PC3 衍生的外泌体导致 NED、细胞增殖和细胞黏附增加。总之，这些发现表明，GHRH 拮抗剂应考虑用于神经内分泌前列腺癌的治疗。
