Mps1 kinase regulates tumor cell viability via its novel role in mitochondria

Zhang, Xiaokang; Ling, Youguo; Guo, Yongyong; Bai, Yuanyuan; Shi, Xiaoqian; Gong, Fuyu; Tan, Pingping; Zhang, Yexi; Wei, Congwen; He, Xian-Hui; Ramirez, Adrian; Liu, X; Cao, Cheng; Zhong, Hui; Xu, Quanbin; Z, Ru

doi:10.1038/cddis.2016.193

Cited by 21 publications

(25 citation statements)

References 67 publications

(89 reference statements)

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“…Indeed, neuroblastoma and PDX cells displayed mitochondrial potential dissipation, the accumulation of cytosolic calcium, activation of the caspase-3, cleavage of PARP, and DNA degradation. These results are in line with previous studies with Mps1 inhibitors or Mps1 silencing confirming the key role of this kinase in the spindle assembly checkpoint function and its vital function, both in vitro and in vivo 20 , 21 , 24 , 25 , 35 , 38 , 39 , 51 , 52 , 54 – 58 .…”

Section: Discussionsupporting

confidence: 92%

“…This particular cell death, known as mitotic catastrophe 40,53 , is an oncosuppressive mechanism for the control of mitosis-incompetent cells. As shown in our models, the 20,21,24,25,35,38,39,51,52,[54][55][56][57][58] .…”

Section: Discussionsupporting

confidence: 61%

“…S2 B). Autophagosome formation was shown to be upregulated upon Mps1 depletion 35 , thus we investigated autophagy in SK-N-Be2c neuroblastoma cells treated with Reversine or Mps-BAY2a. We used Acridine Orange staining and flow cytometry.…”

Section: Resultsmentioning

confidence: 99%

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Inhibition of mitotic kinase Mps1 promotes cell death in neuroblastoma

Serrano

Sime

Abassi

et al. 2020

Sci Rep

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Neuroblastoma is the most common paediatric cancer type. Patients diagnosed with high-risk neuroblastoma have poor prognosis and occasionally tumours relapse. As a result, novel treatment strategies are needed for relapse and refractory neuroblastoma patients. Here, we found that high expression of Mps1 kinase (mitotic kinase Monopolar Spindle 1) was associated with relapsefree neuroblastoma patient outcomes and poor overall survival. Silencing and inhibition of Mps1 in neuroblastoma or PDX-derived cells promoted cell apoptosis via the caspase-dependent mitochondrial apoptotic pathway. The mechanism of cell death upon Mps1 inhibition was dependent on the polyploidization/aneuploidization of the cells before undergoing mitotic catastrophe. Furthermore, tumour growth retardation was confirmed in a xenograft mouse model after Mps1inhibitor treatment. Altogether, these results suggest that Mps1 expression and inhibition can be considered as a novel prognostic marker as well as a therapeutic strategy for the treatment of highrisk neuroblastoma patients. Neuroblastoma is the most common extra-cranial solid tumour of childhood 1,2 causing approximately 10% of all childhood cancer-related deaths 3,4. Neuroblastoma is a very heterogeneous tumour compared to other cancers. It can regress spontaneously, however, in certain cases, can undergo treatment resistance 5,6. The International Neuroblastoma Risk Group (INRG) classifies neuroblastoma tumours into very low-risk, low-risk, intermediaterisk, and high-risk 7,8. Identification of the high-risk group is important for the development of personalised medicine for neuroblastoma patients with poor prognosis. Good prognosis has been observed in children with low-or intermediate-risk after chemotherapy in combination with surgical intervention. High-risk neuroblastoma represent 40% of all diagnosed cases, and these patients have poor prognosis harbouring tumour relapse and chemoresistance, and only 50% will attain long-term survival 9,10. MYCN gene amplification has been observed in less than half of the high-risk tumours 11. In non-MYCN high-risk neuroblastoma, point mutations in TP53 and Anaplastic Lymphoma Kinase (ALK) gene mutation have been observed 12 in less than 10% of neuroblastomas 13. Recently, targeting cell cycle and in particular mitosis has been proposed as an alternative therapeutic strategy for cancer treatment 14. Spindle Assembly Checkpoint or SAC generally monitor proper mitosis by controlling the correct attachment of the chromosomes to the microtubule spindle apparatus via their kinetochores 15. Once the chromosomes are fully arranged on the metaphase plate, the SAC is turned off, and chromosome segregation as well as cell division can be engaged 16. The Mps1 kinase (Monopolar spindle1) is an important regulator of the SAC and it phosphorylates target proteins principally on tyrosines, serines, and threonines 17. The most important function of Mps1 is to ensure proper biorientation of sister chromatids on the mitotic spindle at kinetochores. In early mitosi...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 61%

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Inhibition of mitotic kinase Mps1 promotes cell death in neuroblastoma

Serrano

Sime

Abassi

et al. 2020

Sci Rep

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“…Due to the vital role of Mps1 in cellular function, an imbalance of Mps1 activity is often detrimental to cell survival. For instance, when Mps1 is depleted, mitosis proceeds regardless of proper chromosomal alignment, leading to aberrations in chromosome counts [ 4 ]. It has been well documented that a number of tumor types express abnormally high levels of Mps1.…”

Section: Introductionmentioning

confidence: 99%

Insights into Resistance Mechanisms of Inhibitors to Mps1 C604Y Mutation via a Comprehensive Molecular Modeling Study

Chen

Jiang

et al. 2018

Molecules

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Mono-polar spindle 1 (Mps1/TTK) represents a protein kinase reported to be vital for cell division processes and is generally regarded as an attractive target for the treatment of hepatocellular carcinoma, breast carcinoma, and colon cancer. However, the C604Y mutation has been linked to acquired resistance. Recently, three potential small-molecule inhibitors of Mps1 (i.e., reversine, NMS-P715, and its derivative Cpd-5) were reported for the C604Y mutation that exhibit significant resistance to NMS-P715 and Cpd-5, but retain affinity for reversine. In this study, classical molecular dynamic (MD) simulations, accelerated MD (aMD) simulations, and umbrella sampling (US) simulations were performed to illustrate the resistance mechanisms of inhibitors to Mps1. The classical MD simulations combined with free energy calculations revealed that reversine features similar binding affinity characteristics to both Mps1WT and Mps1C604Y, but both NMS-P715 and Cpd-5 feature much higher binding affinities to Mps1WT than to Mps1C604Y. The major variations were shown to be controlled by electrostatic energy and the conformational change of A-loop-induced entropy increased. The large conformational changes of Mps1C604Y bound to NMS-P715 and Cpd-5 were also observed in aMD simulations. The US simulation results further suggest that reversine and Cpd-5 both exhibit similar dissociation processes from both Mps1WT and Mps1C604Y, but Cpd-5 and NMS-P715 were found to dissociate more easily from Mps1C604Y than from Mps1WT, thus a reduced residence time was responsible for the inhibitors resistance to the C604Y mutation. The physical principles provided by the present study may provide important clues for the discovery and rational design of novel inhibitors to combat the C604Y mutation of Mps1.

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“…A pool of Cyclin B1/Cdk1 localizes to the mitochondria, phosphorylates components of the OXPHOS machinery and increases their activity at the G2/M transition [84] . Some components of the spindle assembly checkpoint (e.g., Mad2, BubR1, p31-comet) have roles in insulin signaling [85] , while others (e.g., Mps1, Survivin) localize to the mitochondria and regulate apoptosis [86,87] . Together, these results indicate extensive regulation of mitochondria functions and/or cell metabolism by the cell cycle machinery.…”

Section: Mitochondria Dynamics Are Regulated By the Cell Cyclementioning

confidence: 99%

Genomic heterogeneity meets cellular energetics: crosstalk between the mitochondria and the cell cycle

Herrera¹,

Azzam²,

Berger³

et al. 2018

JCMT

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Changes in cellular energetics and genomic instability are two characteristics of cancers that have been studied independently. Evidence of cross-talk between mitochondria function and nuclear function has started to emerge, suggesting that these pathways can influence one another. Here we review recent evidence that links the mitochondria and the cell cycle. This evidence indicates bidirectional cross-talk where mitochondria function can regulate the cell cycle and induce genomic instability, and conversely, the cell cycle machinery regulates mitochondria function. Implications for this cross-talk in the development of cancer are discussed.

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Mps1 kinase regulates tumor cell viability via its novel role in mitochondria

Cited by 21 publications

References 67 publications

Inhibition of mitotic kinase Mps1 promotes cell death in neuroblastoma

Inhibition of mitotic kinase Mps1 promotes cell death in neuroblastoma

Insights into Resistance Mechanisms of Inhibitors to Mps1 C604Y Mutation via a Comprehensive Molecular Modeling Study

Genomic heterogeneity meets cellular energetics: crosstalk between the mitochondria and the cell cycle

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