Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, 300211, Tianjin, China.
University of Minnesota, Minnesota, MN, 55455, USA.
Oncogene. 2019 Jun;38(24):4875-4884. doi: 10.1038/s41388-019-0750-5. Epub 2019 Feb 15.
Castration-resistant prostate cancer (CRPC) with neuroendocrine differentiation (NED) is a lethal disease for which effective therapies are urgently needed. The mechanism underlying development of CRPC with NED, however, remains largely uncharacterized. In this study, we explored and characterized the functional role of neurotensin (NTS) in cell line and animal models of CRPC with NED. NTS was acutely induced by androgen deprivation in animal models of prostate cancer (PCa) and activated downstream signaling leading to NED through activation of neurotensin receptor 1 (NTSR1) and neurotensin receptor 3 (NTSR3), but not neurotensin receptor 2 (NTSR2). Our findings also revealed the existence of a CK8/CK14 subpopulation in the LNCaP cell line that expresses high levels of both NTSR1 and NTSR3, and displays an enhanced susceptibility to develop neuroendocrine-like phenotypes upon treatment with NTS. More importantly, NTSR1 pathway inhibition prevented the development of NED and castration resistance in vivo. We propose a novel role of NTS in the development of CRPC with NED, and a possible strategy to prevent the onset of NED by targeting the NTS signaling pathway.
去势抵抗性前列腺癌（CRPC）伴神经内分泌分化（NED）是一种致命疾病，迫切需要有效的治疗方法。然而，CRPC 伴 NED 的发展机制在很大程度上仍未被阐明。在这项研究中，我们探索并描述了神经降压素（NTS）在伴有 NED 的 CRPC 细胞系和动物模型中的功能作用。在前列腺癌（PCa）动物模型中，NTS 被雄激素剥夺急性诱导，并通过激活神经降压素受体 1（NTSR1）和神经降压素受体 3（NTSR3）而不是神经降压素受体 2（NTSR2）激活下游信号，导致 NED。我们的研究结果还揭示了 LNCaP 细胞系中存在 CK8/CK14 亚群，该亚群高水平表达 NTSR1 和 NTSR3，并在接受 NTS 治疗时表现出增强的发展为神经内分泌样表型的易感性。更重要的是，NTSR1 通路抑制可预防体内 NED 和去势抵抗的发展。我们提出了 NTS 在伴有 NED 的 CRPC 发展中的新作用，以及通过靶向 NTS 信号通路来预防 NED 发生的可能策略。
