Caspase 2 in mitotic catastrophe: The terminator of aneuploid and tetraploid cells

Vitale, Ilio; Manic, Gwenola; Castedo, Maria; Kroemer, Guido

doi:10.1080/23723556.2017.1299274

Cited by 27 publications

(22 citation statements)

References 31 publications

(43 reference statements)

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“…5e ). In support of these results, western blotting showed that MASTL depletion increased cleaved-PARP and γ-H2AX, and activated caspase-2, as evidenced by the decrease in procaspase-2, which is a major caspase in the mitotic cell death in response to DNA damage [ 7 ], and decreased phosphorylated ENSA, a substrate of MASTL, in a time-dependent manner in MCF7 and T47D cells (Fig. 5f ).…”

Section: Resultssupporting

confidence: 57%

“…Mitotic catastrophe is a type of cell death that results from abnormal mitosis following DNA damage, such as that caused by irradiation, and is related to premature chromosome condensation and the formation of large cells with multiple micronuclei [ 5 , 6 ]. DNA damage-induced mitotic catastrophe can be driven by the activation of caspases, particularly caspase-2 [ 6 , 7 ]. Recently, it was shown that the activation of caspase-2 in response to DNA damage plays an oncosuppressive role through the reduction of genomic instability and chromosomal aberrations that may promote tumorigenesis [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

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MASTL inhibition promotes mitotic catastrophe through PP2A activation to inhibit cancer growth and radioresistance in breast cancer cells

et al. 2018

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BackgroundAlthough MASTL (microtubule-associated serine/threonine kinase-like) is a key mitotic kinase that regulates mitotic progression through the inactivation of tumor suppressor protein phosphatase 2A (PP2A), the antitumor mechanism of MASTL targeting in cancer cells is still unclear.MethodsMASTL expression was evaluated by using breast cancer tissue microarrays and public cancer databases. The effects of MASTL depletion with siRNAs were evaluated in various breast cancer cells or normal cells. Various methods, including cell viability, cell cycle, soft agar, immunoblotting, immunofluorescence, PP2A activity, live image, and sphere forming assay, were used in this study.ResultsThis study showed the oncosuppressive mechanism of MASTL targeting that promotes mitotic catastrophe through PP2A activation selectively in breast cancer cells. MASTL expression was closely associated with tumor progression and poor prognosis in breast cancer. The depletion of MASTL reduced the oncogenic properties of breast cancer cells with high MASTL expression, but did not affect the viability of non-transformed normal cells with low MASTL expression. With regard to the underlying mechanism, we found that MASTL inhibition caused mitotic catastrophe through PP2A activation in breast cancer cells. Furthermore, MASTL depletion enhanced the radiosensitivity of breast cancer cells with increased PP2A activity. Notably, MASTL depletion dramatically reduced the formation of radioresistant breast cancer stem cells in response to irradiation.ConclusionOur data suggested that MASTL inhibition promoted mitotic catastrophe through PP2A activation, which led to the inhibition of cancer cell growth and a reversal of radioresistance in breast cancer cells.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4600-6) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

MASTL inhibition promotes mitotic catastrophe through PP2A activation to inhibit cancer growth and radioresistance in breast cancer cells

et al. 2018

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“…There are nine genes annotated as being involved in apoptosis, a process that can be initiated if a cell fails a mitotic check point. CASP2, long considered to be an orphan caspase 72 , is recognised as a key factor in driving cell apoptosis (mitotic catastrophe) triggered by mitotic abnormalities, such as defects in chromosomes, mitotic spindles, or the cytokinesis apparatus 73,74 . Other genes within the list await functional validation.…”

Section: Discussionmentioning

confidence: 99%

Assembly of a Parts List of the Human Mitotic Cell Cycle Machinery

Giotti

Chen

Barnett

et al. 2018

Preprint

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13The set of proteins required for mitotic division remains poorly characterised. Here, an 14 extensive series of correlation analyses of human and mouse transcriptomics data was 15 performed to identify genes strongly and reproducibly associated with cells undergoing S/G2-16M phases of the cell cycle. In so doing, a list of 701 cell cycle-associated genes was defined 17and shown that whilst many are only expressed during these phases, the expression of others 18 is also driven by alternative promoters. Of this list, 496 genes have known cell cycle functions, 19whereas 205 were assigned as putative cell cycle genes, 53 of which are functionally 20uncharacterised. Among these, 27 were screened for subcellular localisation revealing many 21to be nuclear localised and at least four to be novel centrosomal proteins. Furthermore, 10 22 others inhibited cell proliferation upon siRNA knockdown. This study presents the first 23comprehensive list of human cell cycle proteins, identifying many new candidate proteins. 24 33 are important therapeutic targets 3 and novel components might present new therapeutic 34opportunities. 36Many of the key proteins required for mitotic division are known from studies in model 37 organisms including yeast, as well as mammalian cells 4,5 . With the aim of identifying all the 38 components of the system, high content analysis platforms have been utilised. For example 39RNAi screens 6-8 , CRISPR/Cas9 9 , proteomics 10,11,12 studies have all proposed lists of cell cycle 40 genes/proteins but a consensus between studies has not emerged. In particular, genome-wide 41transcriptomics studies [13][14][15][16][17][18][19] have identified sets of transcripts sequentially regulated during 42 the cell cycle phases in multiple species but comparison of results from four studies of 43 different human cell lines identified only 96 genes in common 15 . Our reanalysis of these data, 44taking account of some of the technical variables, suggested that the true concordance of the 45 cell cycle transcriptional network across cell types is much greater 20 . Furthermore, our 46analyses of large collections of tissue and cell transcriptomics data commonly identify a large 47 cluster of cell cycle transcripts whose expression is elevated in cells or tissues with a high 48 mitotic index [21][22][23][24][25] . 49 50We report here on a data driven curation exercise aimed at identifying the cohort of genes 51up-regulated in all human cell types from the G1/S boundary through to the completion of M 52 phase (S/G2-M). There are of course, many growth-associated transcriptional regulatory 53 events including activation of cyclins, cyclin-dependent kinases and E2F transcription factors, 54 that occur during G1 and are a precondition for entry into S phase 26 , but these are not the 55 focus of this study. We monitored genome-wide gene expression in primary human dermal 56fibroblasts (NHDF) cells as they synchronously enter the cell cycle from a resting state (G0). 57Using network co-expression analysis and clustering of ...

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“…These round of polyploidy engender defective mitosis and non-viable aneuploid daughter cells that die by the activation of the mitochondrial pathway of cell death. This particular death is called mitotic catastrophe 38,40,41 . We found similar results using the neuroblastoma cell lines SK-N-F1, SK-N-AS, IMR32, SK-N-RA and SK-N-DZ treated with Reversine or Mps-BAY2a.…”

Section: Mps1 Inhibition Provokes the Mitochondrial Pathway Of Apoptomentioning

confidence: 99%

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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Caspase 2 in mitotic catastrophe: The terminator of aneuploid and tetraploid cells

Cited by 27 publications

References 31 publications

MASTL inhibition promotes mitotic catastrophe through PP2A activation to inhibit cancer growth and radioresistance in breast cancer cells

MASTL inhibition promotes mitotic catastrophe through PP2A activation to inhibit cancer growth and radioresistance in breast cancer cells

Assembly of a Parts List of the Human Mitotic Cell Cycle Machinery

Inhibition of mitotic kinase Mps1 promotes cell death in neuroblastoma

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