Chalcomoracin is a potent anticancer agent acting through triggering Oxidative stress via a mitophagy- and paraptosis-dependent mechanism
Chalcomoracin is a potent anticancer agent acting through triggering Oxidative stress via a mitophagy- and paraptosis-dependent mechanism
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Chalcomoracin 是一种有效的抗癌剂，通过线粒体自噬和凋亡依赖性机制触发氧化应激发挥作用
DOI：
10.1038/s41598-018-27724-3
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发表时间：
2018-06-22
影响因子：
4.6
通讯作者：
Tian, Jingkui
中科院分区：
文献类型：
--
作者：
Han, Haote;Chou, Chih-Chien;Tian, Jingkui
Chalocomoracin (CMR), one of the major secondary metabolites found in fungus-infected mulberry leaves, is a potent anticancer agent. However, its anticancer mechanism remains elusive. Here, we demonstrated the potent anti-tumor activity and molecular mechanism of CMR both in vitro and in vivo. We showed for the first time that CMR treatment markedly promoted paraptosis along with extensive cytoplasmic vacuolation derived from the endoplasmic reticulum, rather than apoptosis, in PC-3 and MDA-MB-231cell lines. Additional studies revealed that ectopic expression of Myc-PINK1 (PTEN-induced kinase 1), a key regulator of mitophagy, rendered LNCap cells susceptible to CMR-induced paraptosis, suggesting that the mitophagy-dependent pathway plays a crucial role in inducing paraptosis by activating PINK1. CMR treatment directly upregulated PINK1 and downregulated Alix genes in MDA-MB-231 and PC-3 cell lines. Furthermore, mitophagy signaling and paraptosis with cytoplasmic vacuolation could be blocked by antioxidant N-acetylcysteine (NAC), indicating the novel pathway was triggered by reactive oxygen species (ROS) production. An in vivo MDA-MB-231 xenograft tumor model revealed that CMR suppressed tumor growth by inducing vacuolation production through the same signal changes as those observed in vitro. These data suggest that CMR is a potential therapeutic entity for cancer treatment through a non-apoptotic pathway.
