Dwivedi Shubham, Bautista Maricris, Shrestha Sanskriti, Elhasasna Hussain, Chaphekar Tanaya, Vizeacoumar Frederick S, Krishnan Anand
Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada.
Cameco MS Neuroscience Research Centre (CMSNRC), Saskatoon, SK, S7K 0M7, Canada.
Cell Death Discov. 2021 Nov 22;7(1):364. doi: 10.1038/s41420-021-00752-1.
The progression of prostate cancer (PC) into neuroendocrine prostate cancer (NEPC) is a major challenge in treating PC. In NEPC, the PC cells undergo neuroendocrine differentiation (NED); however, the exact molecular mechanism that triggers NED is unknown. Peripheral nerves are recently shown to promote PC. However, their contribution to NEPC was not studied well. In this study, we explored whether sympathetic neurosignaling contributes to NED. We found that human prostate tumors from patients that later developed metastases and castration-resistant prostate cancer (CRPC), a stage preceding to NEPC, have high sympathetic innervations. Our work revealed that high concentrations of the sympathetic neurotransmitter norepinephrine (NE) induces NED-like changes in PC cells in vitro, evident by their characteristic cellular and molecular changes. The NE-mediated NED was effectively inhibited by the Adrβ2 blocker propranolol. Strikingly, propranolol along with castration also significantly inhibited the development and progression of NEPC in vivo in an orthotopic NEPC model. Altogether, our results indicate that the NE-Adrβ2 axis is a potential therapeutic intervention point for NEPC.
前列腺癌（PC）进展为神经内分泌前列腺癌（NEPC）是治疗PC的一项重大挑战。在NEPC中，PC细胞会经历神经内分泌分化（NED）；然而，触发NED的确切分子机制尚不清楚。最近研究表明外周神经会促进PC发展。然而，它们对NEPC的作用尚未得到充分研究。在本研究中，我们探究了交感神经信号是否有助于NED。我们发现，来自后来发生转移和去势抵抗性前列腺癌（CRPC，NEPC之前的一个阶段）患者的人类前列腺肿瘤具有高度的交感神经支配。我们的研究表明，高浓度的交感神经递质去甲肾上腺素（NE）在体外可诱导PC细胞发生类似NED的变化，其特征性的细胞和分子变化可证明这一点。NE介导的NED可被肾上腺素能β2受体阻滞剂普萘洛尔有效抑制。引人注目的是，在原位NEPC模型中，普萘洛尔与去势联合使用还能显著抑制NEPC在体内的发生和发展。总之，我们的结果表明NE - 肾上腺素能β2受体轴是NEPC潜在的治疗干预靶点。
