Mps1 kinase regulates tumor cell viability via its novel role in mitochondria.
Mps1 kinase regulates tumor cell viability via its novel role in mitochondria.
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MPS1 激酶通过其在线粒体中的新作用调节肿瘤细胞活力
DOI：
10.1038/cddis.2016.193
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发表时间：
2016-07-07
影响因子：
9
通讯作者：
Ma RZ
中科院分区：
文献类型：
--
作者：
Zhang X;Ling Y;Guo Y;Bai Y;Shi X;Gong F;Tan P;Zhang Y;Wei C;He X;Ramirez A;Liu X;Cao C;Zhong H;Xu Q;Ma RZ
靶向有丝分裂激酶单极纺锤体1（Mps1）用于肿瘤治疗已经研究了多年。尽管有人认为Mps1通过其在纺锤体组装检查点（SAC）中的作用来调节细胞活力，但其潜在机制仍然不太明确。奋进揭示高水平的有丝分裂激酶Mps1在结肠癌发展中的作用，我们意外地发现细胞存活所需的Mps1的量远远超过在非整倍体细胞系中维持SAC所需的量。这表明除了SAC之外，Mps1的其他功能也用于维持细胞活力。Mps1调节细胞活力独立于其在胞质分裂中的作用，因为从中期到胞质分裂的Mps1的遗传耗竭既不影响胞质分裂也不影响细胞活力。此外，我们开发了一种单周期抑制策略，允许破坏Mps1功能只在有丝分裂。使用这种策略，我们发现Mps1在有丝分裂中的功能对细胞活力至关重要，因为用Mps1抑制剂短期治疗有丝分裂结肠癌细胞系足以引起细胞死亡。有趣的是，Mps1抑制剂与微管解聚药物协同促进多倍化，但不抑制肿瘤细胞生长。最后，我们发现Mps1可以通过其C端片段与电压依赖性阴离子通道1（VDAC 1）结合而被募集到线粒体。这种相互作用对于细胞活力是必不可少的，因为相互作用缺陷的Mps1突变体不能维持细胞活力，导致细胞色素c的释放。同时，VDAC 1的剥夺可以使肿瘤细胞对Mps 1诱导的细胞死亡的丧失不敏感。总的来说，我们得出结论，新的线粒体功能Mps1的抑制足以杀死肿瘤细胞。
Targeting mitotic kinase monopolar spindle 1 (Mps1) for tumor therapy has been investigated for many years. Although it was suggested that Mps1 regulates cell viability through its role in spindle assembly checkpoint (SAC), the underlying mechanism remains less defined. In an endeavor to reveal the role of high levels of mitotic kinase Mps1 in the development of colon cancer, we unexpectedly found the amount of Mps1 required for cell survival far exceeds that of maintaining SAC in aneuploid cell lines. This suggests that other functions of Mps1 besides SAC are also employed to maintain cell viability. Mps1 regulates cell viability independent of its role in cytokinesis as the genetic depletion of Mps1 spanning from metaphase to cytokinesis affects neither cytokinesis nor cell viability. Furthermore, we developed a single-cycle inhibition strategy that allows disruption of Mps1 function only in mitosis. Using this strategy, we found the functions of Mps1 in mitosis are vital for cell viability as short-term treatment of mitotic colon cancer cell lines with Mps1 inhibitors is sufficient to cause cell death. Interestingly, Mps1 inhibitors synergize with microtubule depolymerizing drug in promoting polyploidization but not in tumor cell growth inhibition. Finally, we found that Mps1 can be recruited to mitochondria by binding to voltage-dependent anion channel 1 (VDAC1) via its C-terminal fragment. This interaction is essential for cell viability as Mps1 mutant defective for interaction fails to main cell viability, causing the release of cytochrome c. Meanwhile, deprivation of VDAC1 can make tumor cells refractory to loss of Mps1-induced cell death. Collectively, we conclude that inhibition of the novel mitochondrial function Mps1 is sufficient to kill tumor cells.