Cell death by mitotic catastrophe: a molecular definition

Castedo, Maria; Perfettini, Jean-Luc; Roumier, Thomas; Andréau, Karine; Medema, René H.; Kroemer, Guido

doi:10.1038/sj.onc.1207528

Cited by 1,113 publications

(1,002 citation statements)

References 149 publications

Supporting

Mentioning

928

Contrasting

Unclassified

Order By: Relevance

“…Accumulated aneuploid cells gradually induced cell death, while decreasing the proportion of aneuploid cells after irradiation. Survivin and p53 are believed to play an important role in the coupling of abnormal mitotic progression to the onset of mitotic catastrophe (Castedo et al, 2004). Our findings therefore suggest that advanced CIN, such as that observed in a survivin-inhibited state, would therefore reduce the viability after genotoxic stress, including irradiation, thus leading to mitotic cell death and resulting in enhanced radiosensitivity.…”

Section: Discussionmentioning

confidence: 73%

Centrosome amplification induced by survivin suppression enhances both chromosome instability and radiosensitivity in glioma cells

et al. 2008

View full text Add to dashboard Cite

Glioblastoma is characterised by invasive growth and a high degree of radioresistance. Survivin, a regulator of chromosome segregation, is highly expressed and known to induce radioresistance in human gliomas. In this study, we examined the effect of survivin suppression on radiosensitivity in malignant glioma cells, while focusing on centrosome aberration and chromosome instability (CIN). We suppressed survivin by small interfering RNA transfection, and examined the radiosensitivity using a clonogenic assay and a trypan blue exclusion assay in U251MG (p53 mutant) and D54MG (p53 wild type) cells. To assess the CIN status, we determined the number of centrosomes using an immunofluorescence analysis, and the centromeric copy number by fluorescence in situ hybridisation. As a result, the radiosensitisation differed regarding the p53 status as U251MG cells quickly developed extreme centrosome amplification ( ¼ CIN) and enhanced the radiosensitivity, while centrosome amplification and radiosensitivity increased more gradually in D54MG cells. TUNEL assay showed that survivin inhibition did not lead to apoptosis after irradiation. This cell death was accompanied by an increased degree of aneuploidy, suggesting mitotic cell death. Therefore, survivin inhibition may be an attractive therapeutic target to overcome the radioresistance while, in addition, proper attention to CIN (centrosome number) is considered important for improving radiosensitivity in human glioma.

show abstract

Section: Discussionmentioning

confidence: 73%

Centrosome amplification induced by survivin suppression enhances both chromosome instability and radiosensitivity in glioma cells

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Recent human and experimental studies in HIVAN, FSGS, MCD and IgAN have reported MC as a previous unrecognized cause of podocyte loss 13, 14. MC as a form of cell death was first observed in irradiated cancer tissues, characterized by abnormal nuclear configurations and spatial distribution of chromosomes and accompanied by changes in cell cycle checkpoint proteins, aurora kinases and cyclin B1‐dependent kinase Cdk1 levels 29, 30. Binucleated or multi‐nucleated cells with enlarged cytoplasm and nuclear changes are recognized features of aberrant podocyte mitosis 31.…”

Section: Discussionmentioning

confidence: 99%

MDM2 is implicated in high‐glucose‐induced podocyte mitotic catastrophe via Notch1 signalling

Tang

Lei

Wang

et al. 2017

J Cellular Molecular Medi

View full text Add to dashboard Cite

Podocyte injury and depletion are essential events involved in the pathogenesis of diabetic nephropathy (DN). As a terminally differentiated cell, podocyte is restricted in ‘post‐mitosis’ state and unable to regenerate. Re‐entering mitotic phase will cause podocyte disastrous death which is defined as mitotic catastrophe (MC). Murine double minute 2 (MDM2), a cell cycle regulator, is widely expressed in renal resident cells including podocytes. Here, we explore whether MDM2 is involved in podocyte MC during hyperglycaemia. We found aberrant mitotic podocytes with multi‐nucleation in DN patients. In vitro, cultured podocytes treated by high glucose (HG) also showed an up‐regulation of mitotic markers and abnormal mitotic status, accompanied by elevated expression of MDM2. HG exposure forced podocytes to enter into S phase and bypass G2/M checkpoint with enhanced expression of Ki67, cyclin B1, Aurora B and p‐H3. Genetic deletion of MDM2 partly reversed HG‐induced mitotic phase re‐entering of podocytes. Moreover, HG‐induced podocyte injury was alleviated by MDM2 knocking down but not by nutlin‐3a, an inhibitor of MDM2‐p53 interaction. Interestingly, knocking down MDM2 or MDM2 overexpression showed inhibition or activation of Notch1 signalling, respectively. In addition, genetic silencing of Notch1 prevented HG‐mediated podocyte MC. In conclusion, high glucose up‐regulates MDM2 expression and leads to podocyte MC. Notch1 signalling is an essential downstream pathway of MDM2 in mediating HG‐induced MC in podocytes.

show abstract

“…The cells that were large (absent of cytoplasmic shrinkage) and contained separate micronuclei with evenly stained chromatin (absence of chromatin condensation) were defined as multinucleated cells as reported previously. 19,25,26 The percentage of multimicronucleated cells was determined after scoring more than 100 nuclei for each experiment. Each experiment was repeated at least three times.…”

Section: Discussionmentioning

confidence: 99%

DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells

et al. 2006

View full text Add to dashboard Cite

Although autophagy enhances cell survival in nutrient-deprived cells by increasing adenosine triphosphate (ATP) production, it remains unclear if autophagy functions similarly in cells treated with cytotoxic chemotherapy agents. To address this issue, we measured both the ability of DNA damaging agents (Temozolomide, and Etoposide) to induce an autophagy-dependent production of ATP, and the effects of modulation of autophagy on drug-induced cell death. Both drugs induced an autophagyassociated increase in ATP production in multiple glioma cell lines. The drug-induced ATP surge could not be blocked by glucose starvation, but could be blocked by preincubation with the autophagy inhibitor 3-methyladenine (3-MA), an siRNA targeting beclin 1, or the mitochondrial inhibitor oligomycin. Inhibition of autophagy-induced ATP production increased nonapoptotic cell death associated with micronucleation, while restoration of the 3-MA-inhibited ATP surge by addition of pyruvate suppressed cell death. These results show that DNA damaging agents induce an autophagy-associated ATP surge that protects cells and may contribute to drug resistance. Autophagy is a process by which subcellular constituents are degraded in autophagosomes/autolysosomes in response to stress. 1 Whereas growth factors enhance the ability of metazoan cells to take up extracelluar nutrients and suppress autophagy, deprivation of either growth factors or extracellular nutrients leads to decreased nutrient uptake and derepression of autophagy. The catabolic autophagy process is believed to allow starving cells to support adenosine triphosphate (ATP) production and avoid cell death. 2,3 The autophagic process is regulated by both class I and class III phosphatidylinositol 3-kinase (PI3K) pathways. 2,4,5 Mammalian target of Rapamycin (mTOR) functions downstream of the class-I PI3K/Akt, and is a key negative regulator of autophagy. In this role, mTOR serves as a metabolic sensor that coordinates crosstalk between nutrient availability and autophagy. 6,7 In contrast, class III PI3K positively regulates autophagy. The formation of a preautophagosomal isolation membrane that encloses cytoplasmic cargo is positively regulated by phosphatidylinositol 3-phosphate, the products of class III PI3K phosphorylation. 4 It has also been suggested that the trafficking of autophagosomes is regulated by class III PI3Ks, 4,5 an idea supported by the observation that 3-methyladenine (3-MA), which inhibits class III PI3K activity, also inhibits autophagosome formation and is widely used as an autophagy inhibitor. 5 It is also known that autophagy is induced in cancer cells derived from tissues such as breast, colon, prostate and brain in response to a variety of anticancer therapies. 3,8 However, autophagy in response to these drugs can produce different outcomes, in some cases promoting cell adaptation and survival similar to what is seen in nutrient deprived cells, while in other cases, inducing programmed cell death type. The role of drug-induced autophagy in cell death or surv...

show abstract

Cell death by mitotic catastrophe: a molecular definition

Cited by 1,113 publications

References 149 publications

Centrosome amplification induced by survivin suppression enhances both chromosome instability and radiosensitivity in glioma cells

Centrosome amplification induced by survivin suppression enhances both chromosome instability and radiosensitivity in glioma cells

MDM2 is implicated in high‐glucose‐induced podocyte mitotic catastrophe via Notch1 signalling

DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells

Contact Info

Product

Resources

About