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Mitochondrial cytochrome P450 (CYP) 1B1 is responsible for melatonin‐induced apoptosis in neural cancer cells
Journal of Pineal Research ( IF 10.3 ) Pub Date : 2018-03-25 , DOI: 10.1111/jpi.12478
Zhenlong Yu 1 , Xiangge Tian 1 , Yuling Peng 1 , Zheng Sun 1 , Chao Wang 1 , Ning Tang 1 , Bin Li 2 , Yuqing Jian 2 , Wei Wang 2 , Xiaokui Huo 1 , Xiaochi Ma 1
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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.

中文翻译:

线粒体细胞色素 P450 (CYP) 1B1 负责褪黑素诱导的神经癌细胞凋亡

褪黑激素是一种内源性吲哚胺,在从细菌到哺乳动物的各种生物体中具有广泛的生物学功能。有证据表明,褪黑激素可促进癌细胞凋亡,并增强动物和临床研究中化疗的抗肿瘤活性。然而,褪黑激素代谢和癌细胞中的关键代谢靶点仍然未知。在本研究中,使用U118和SH-SY5Y肿瘤细胞系来研究褪黑激素在癌细胞中的代谢途径。有趣的是,褪黑素对 SH-SY5Y 细胞增殖的抑制作用比 U118 细胞更有效。相反,对正常细胞不存在这种抑制作用。褪黑激素的抗肿瘤作用与其代谢物N-乙酰血清素 (NAS) 呈正相关。出乎意料的是,CYP1B1首次被发现位于肿瘤细胞的线粒体中,它代谢褪黑激素原位形成NAS,随后触发癌细胞中线粒体依赖性细胞凋亡。在正常细胞中,NAS 不会诱导细胞凋亡。在人类肿瘤组织中也检测到 CYP1B1 表达存在显着的个体差异。这些发现提供了有关褪黑激素在线粒体水平上的抗肿瘤作用的新机制。因此,我们假设线粒体中 CYP1B1 的过度表达会显着增强褪黑激素的抗肿瘤作用。线粒体 CYP1B1 有可能作为特定靶点来改变褪黑激素对癌症患者的治疗和生物学作用。
更新日期:2018-03-25
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