Dynamin-related protein 1 is involved in micheliolide-induced breast cancer cell death.
Dynamin-related protein 1 is involved in micheliolide-induced breast cancer cell death.
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动力相关蛋白 1 参与米凯内酯诱导的乳腺癌细胞死亡。
DOI：
10.2147/ott.s91805
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发表时间：
2015
影响因子：
4
通讯作者：
Tong Z
中科院分区：
文献类型：
--
作者：
Jia Y;Zhou L;Tian C;Shi Y;Wang C;Tong Z
动力蛋白相关蛋白1（Dynamin-related protein 1，Drp 1）是新近发现的肿瘤发生、迁移、增殖和化疗敏感性的治疗靶点。因此，专注于靶向Drp 1及其相关信号通路的治疗策略为解决传统癌症疗法的无效性铺平了新的道路。愈创木萜类倍半萜内酯Micheli（MCL）可选择性地根除急性髓系白血病干细胞或祖细胞。但是MCL对癌细胞线粒体动力学的影响仍然没有得到很好的证明。在这项研究中，我们发现MCL抑制MCF-7人乳腺癌细胞的生长，伴随着线粒体分裂增加和Drp 1的上调。从野生型或显性阴性突变型Drp 1的过表达实验中获得的结果表明，Drp 1是诱导MDA-MB-231和MCF-7细胞死亡所必需且充分的。此外，线粒体膜电位下降，而活性氧（ROS）的产生，细胞色素c的释放，和PARP裂解后，过量表达野生型Drp 1增强。另一方面，过量表达Drp 1-K38 A（Drp 1的显性负突变体）使细胞免于凋亡增加，证实了MCL诱导的Drp 1在观察到的凋亡中的作用。最后，在乳腺癌细胞中，MCL诱导的Drp 1介导的细胞死亡可以被N-乙酰基-L-半胱氨酸（ROS清除剂）逆转。综上所述，本研究显示了Drp 1在MCL诱导的乳腺癌细胞死亡中的新作用，可能通过调节ROS-线粒体凋亡途径。
Dynamin-related protein 1 (Drp1) is a newly discovered therapeutic target for tumor initiation, migration, proliferation, and chemosensitivity. Thus, therapeutic strategies that focus on targeting Drp1 and its related signaling pathway pave a new way to address the ineffectiveness of traditional cancer therapies. Micheliolide (MCL), a guaianolide sesquiterpene lactone, can selectively eradicate acute myeloid leukemia stem or progenitor cells. But the effect of MCL on the mitochondrial dynamics of cancer cells is still not well demonstrated. In this study, we show that MCL inhibited the growth of MCF-7 human breast cancer cells, accompanied by increased mitochondrial fission and upregulation of Drp1. The results obtained from overexpression experiments of wild or dominant-negative mutant type of Drp1 demonstrate that Drp1 is both necessary and sufficient to induce MDA-MB-231 and MCF-7 cell death. Furthermore, mitochondrial membrane potential decreased, whereas reactive oxygen species (ROS) generation, cytochrome c release, and PARP cleavage were enhanced after overexpression of Drp1 wild type. On the other hand, overexpression of Drp1-K38A (a dominant-negative mutant of Drp1) rescued cells from increased apoptosis, confirming the role of MCL-induced Drp1 in the observed apoptosis. Finally, MCL-induced Drp1-mediated cell death could be reversed by N-acetyl-L-cysteine (the ROS scavenger) in breast cancer cells. Taken together, the present study shows a novel role for Drp1 in MCL-induced breast cancer cell death, potentially through regulation of ROS–mitochondrial apoptotic pathway.