Academy of Integrative Medicine, College of Pharmacy, Dalian Medical University, Dalian, China.
TCM and Ethnomedicine Innovation & Development International Laboratory, Sino-Pakistan TCM and Ethnomedicine Research Center, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China.
J Pineal Res. 2018 Aug;65(1):e12478. doi: 10.1111/jpi.12478. Epub 2018 Mar 25.
Melatonin is an endogenous indoleamine with a wide range of biological functions in the various organisms from bacteria to mammals. Evidence indicates that melatonin facilitates apoptosis in cancer cells and enhances the antitumor activity of chemotherapy in animals and clinical studies. However, the melatonin metabolism and the key metabolic targets in cancer cells still remain unknown. In this study, U118 and SH-SY5Y tumor cell lines were used to investigate the metabolic pathways of melatonin in cancer cells. Interestingly, the inhibitory effect of melatonin on proliferation in SH-SY5Y cells is more potent than that in U118 cells. In contrast, this inhibitory effect on the normal cells is absent. The antitumor effects of melatonin are positively associated with its metabolite N-acetylserotonin (NAS). Unexpectedly, CYP1B1 is, for first time, identified to localize in the mitochondria of tumor cells, and it metabolizes melatonin to form NAS in situ, which subsequently triggers mitochondria-dependent apoptosis in cancer cells. In normal cells, NAS does not induce apoptosis. A remarkable individual variation on CYP1B1 expression was also detected in human tumor tissue. These findings provide the novel mechanisms regarding the antitumor effects of melatonin in the level of mitochondria. Thus, we hypothesize that CYP1B1 overexpression in mitochondria would significantly enhance the antitumor effects of melatonin. Mitochondrial CYP1B1 can potentially serve as a specific target to modify the therapeutic and biological effects of melatonin on cancer patients.
褪黑素是一种内源性吲哚胺，在从细菌到哺乳动物的各种生物中具有广泛的生物学功能。有证据表明，褪黑素促进癌细胞凋亡，并增强动物和临床研究中化疗的抗肿瘤活性。然而，褪黑素代谢及其在癌细胞中的关键代谢靶标仍不清楚。在这项研究中，使用 U118 和 SH-SY5Y 肿瘤细胞系来研究癌细胞中褪黑素的代谢途径。有趣的是，褪黑素对 SH-SY5Y 细胞增殖的抑制作用比 U118 细胞更强。相比之下，这种对正常细胞的抑制作用不存在。褪黑素的抗肿瘤作用与其代谢物 N-乙酰色胺（NAS）呈正相关。出乎意料的是，CYP1B1 首次被鉴定为定位于肿瘤细胞的线粒体中，它将褪黑素代谢为原位 NAS，随后触发癌细胞中线粒体依赖性凋亡。在正常细胞中，NAS 不会诱导细胞凋亡。在人类肿瘤组织中还检测到 CYP1B1 表达的显著个体差异。这些发现提供了关于褪黑素在线粒体水平抗肿瘤作用的新机制。因此，我们假设线粒体中 CYP1B1 的过表达将显著增强褪黑素的抗肿瘤作用。线粒体 CYP1B1 可以作为一种特定的靶点，来修饰褪黑素对癌症患者的治疗和生物学效应。
