title: Mps1 kinase regulates tumor cell viability via its novel role in mitochondria.
abstract: 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.
authors.affiliation: State Key Laboratory for Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Beijing Institute of Biotechnology, Beijing 100850, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ling
authors.affiliation: State Key Laboratory for Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.|Graduate School, University of the Chinese Academy of Sciences, Beijing 100149, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Beijing Institute of Biotechnology, Beijing 100850, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Bai
authors.affiliation: State Key Laboratory for Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.|Graduate School, University of the Chinese Academy of Sciences, Beijing 100149, China.
authors.forename: X
authors.initials: X
authors.lastname: Shi
authors.affiliation: State Key Laboratory for Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.|Graduate School, University of the Chinese Academy of Sciences, Beijing 100149, China.
authors.forename: F
authors.initials: F
authors.lastname: Gong
authors.affiliation: State Key Laboratory for Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: P
authors.initials: P
authors.lastname: Tan
authors.affiliation: Beijing Institute of Biotechnology, Beijing 100850, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Beijing Institute of Biotechnology, Beijing 100850, China.
authors.forename: C
authors.initials: C
authors.lastname: Wei
authors.affiliation: Beijing Institute of Biotechnology, Beijing 100850, China.
authors.forename: X
authors.initials: X
authors.lastname: He
authors.affiliation: University of Colorado at Boulder, Boulder, CO 80302, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ramirez
authors.affiliation: University of Colorado at Boulder, Boulder, CO 80302, USA.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: Beijing Institute of Biotechnology, Beijing 100850, China.
authors.forename: C
authors.initials: C
authors.lastname: Cao
authors.affiliation: Beijing Institute of Biotechnology, Beijing 100850, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhong
authors.affiliation: Beijing Institute of Biotechnology, Beijing 100850, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Xu
authors.affiliation: State Key Laboratory for Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.|Graduate School, University of the Chinese Academy of Sciences, Beijing 100149, China.
authors.forename: R Z
authors.initials: RZ
authors.lastname: Ma
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism*; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D048749:Cytokinesis; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints; D008928:Mitochondria / Q000378:metabolism*; D008938:Mitosis; D011123:Polyploidy; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D050995:Voltage-Dependent Anion Channel 1; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human