Shui Xue, Ren Xuehua, Xu Rong, Xie Qinghua, Hu Yaohua, Qin Jing, Meng Han, Zhang Caiqin, Zhao Jumei, Shi Changhong
Division of Cancer Biology, Laboratory Animal Center, Fourth Military Medical University, 710032, Xi'an, Shaanxi, China; School of Basic Medical Sciences, Medical College of Yan'an University, 580 Bao-Ta Street, 716000, Yanan, China.
Shaanxi Stem Cell Engineering and Technology Research Center, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, China.
Biochem Biophys Res Commun. 2022 May 28;606:135-141. doi: 10.1016/j.bbrc.2022.03.096. Epub 2022 Mar 23.
Neuroendocrine transdifferentiation (NED) of prostate cancer (PCa) is the main cause of failure of androgen receptor inhibitor treatment. However, the molecular mechanisms underlying the development of NEPC, especially treatment-induced NEPC, remain unclear. Emerging evidence indicates that elevated monoamine oxidase A (MAOA) contribute to the proliferation, cell stemness, and bone metastasis in PCa. Here, we generated an enzalutamide-induced NED cell model to assess the role of MAOA during NED. Overall, MAOA expression was significantly increased upon Enz long-term exposure and was required for neuroendocrine marker expression. In particular, Enz was found to induce NED via the MAOA/mTOR/HIF-1α signaling axis. Further analyses revealed that the MAOA inhibitor clorgyline(CLG) may bring multiple benefits to CRPC patients, including better therapeutic effect and delays NED. These findings suggest that MAOA may be an important target for the development of anti-NED therapies, thereby providing a novel strategy for the combined application of CLG and AR inhibitors in the clinic.
前列腺癌（PCa）的神经内分泌转分化（NED）是雄激素受体抑制剂治疗失败的主要原因。然而，神经内分泌前列腺癌（NEPC）发生发展的分子机制，尤其是治疗诱导的NEPC的分子机制仍不清楚。新出现的证据表明，单胺氧化酶A（MAOA）水平升高促进了PCa的增殖、细胞干性和骨转移。在此，我们构建了一种恩杂鲁胺诱导的NED细胞模型，以评估MAOA在NED过程中的作用。总体而言，长期暴露于恩杂鲁胺后，MAOA表达显著增加，且其对于神经内分泌标志物的表达是必需的。特别地，发现恩杂鲁胺通过MAOA/mTOR/HIF-1α信号轴诱导NED。进一步分析表明，MAOA抑制剂氯吉兰（CLG）可能给去势抵抗性前列腺癌（CRPC）患者带来多种益处，包括更好的治疗效果和延缓NED。这些发现提示，MAOA可能是抗NED疗法开发的一个重要靶点，从而为CLG与雄激素受体（AR）抑制剂在临床上的联合应用提供了一种新策略。
