Involvement of p38α in the mitotic progression of<i>p53<sup>-/-</sup></i>tetraploid cells

Vitale, Ilio; Jèmaà, Mohamed; Senovilla, Laura; Galluzzi, Lorenzo; Rello-Varona, Santiago; Métivier, Didier; Ripoche, Hugues; Lazar, Vladimir; Dessen, Philippe; Castedo, Maria; Kroemer, Guido

doi:10.4161/cc.9.14.12254

Cited by 10 publications

(8 citation statements)

References 48 publications

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“…Though p38α has been shown to be involved in mitotic progression of p53 -/-tetraploids, we could not find the effect in our experimental conditions. 24 Our results clearly indicate a differential effect of Aurora A kinase inhibition on inhibiting cell growth. In contrast to Aurora B inhibition, which induces polyploidy in all cells, Aurora A inhibition will induce polyploidy or apoptosis according to the cells p53 status.…”

Section: Methodsmentioning

confidence: 48%

The induction of polyploidy or apoptosis by the Aurora A kinase inhibitor MK8745 is p53-dependent

Nair¹,

Ho²,

Schwartz³

2012

Cell Cycle

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Section: Methodsmentioning

confidence: 48%

The induction of polyploidy or apoptosis by the Aurora A kinase inhibitor MK8745 is p53-dependent

Nair¹,

Ho²,

Schwartz³

2012

Cell Cycle

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“…Recently, Vitale et al showed that p38α is essential to generate tetraploidy in p53 −/− cells ( Vitale et al, 2010 ). Losmapimod and SB203580 have been reported to inhibit both the p38 MAPK α and β isoforms ( Willette et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization

Yeung

Yin

et al. 2018

EBioMedicine

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The epidermal growth factor receptor (EGFR) is known to play a critical role in non-small cell lung cancer (NSCLC). Constitutively active EGFR mutations, including in-frame deletion in exon 19 and L858R point mutation in exon 21, contribute about 90% of all EGFR-activating mutations in NSCLC. Although oral EGFR-tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, show dramatic clinical efficacy with significantly prolonged progression-free survival in patients harboring these EGFR-activating mutations, most of these patients will eventually develop acquired resistance. Researchers have recently named genomic instability as one of the hallmarks of cancer. Genomic instability usually involves a transient phase of polyploidization, in particular tetraploidization. Tetraploid cells can undergo asymmetric cell division or chromosome loss, leading to tumor heterogeneity and multidrug resistance. Therefore, identification of signaling pathways involved in tetraploidization is crucial in overcoming drug resistance. In our present study, we found that gefitinib could activate YAP-MKK3/6-p38 MAPK-STAT3 signaling and induce tetraploidization in gefitinib-resistance cells. Using p38 MAPK inhibitors, SB203580 and losmapimod, we could eliminate gefitinib-induced tetraploidization and overcome gefitinib-resistance. In addition, shRNA approach to knockdown p38α MAPK could prevent tetraploidy formation and showed significant inhibition of cancer cell growth. Finally, in an in vivo study, losmapimod could successfully overcome gefitinib resistance using an in-house established patient-derived xenograft (PDX) mouse model. Overall, these findings suggest that losmapimod could be a potential clinical agent to overcome gefitinib resistance in NSCLC.

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“…However, some recent studies suggested that a small proportion of daughter cells from MM that inherited an appropriate expression profile of genes critical for cell viability and growth through achieving specific chromosome complements could survive or even gain long-term viability. 34,42,43 In our experiment, live cell imaging combined with FISH data unequivocally demonstrated that the segregation pattern in MM was random. On the other hand, multipolar divisions predominantly produced particular chromosome compositions.…”

Section: Discussionmentioning

confidence: 87%

Rapid proliferation of daughter cells lacking particular chromosomes due to multipolar mitosis promotes clonal evolution in colorectal cancer cells

et al. 2012

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Involvement of p38α in the mitotic progression ofp53^-/-tetraploid cells

Cited by 10 publications

References 48 publications

The induction of polyploidy or apoptosis by the Aurora A kinase inhibitor MK8745 is p53-dependent

The induction of polyploidy or apoptosis by the Aurora A kinase inhibitor MK8745 is p53-dependent

Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization

Rapid proliferation of daughter cells lacking particular chromosomes due to multipolar mitosis promotes clonal evolution in colorectal cancer cells

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Involvement of p38α in the mitotic progression ofp53-/-tetraploid cells

Cited by 10 publications

References 48 publications

The induction of polyploidy or apoptosis by the Aurora A kinase inhibitor MK8745 is p53-dependent

The induction of polyploidy or apoptosis by the Aurora A kinase inhibitor MK8745 is p53-dependent

Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization

Rapid proliferation of daughter cells lacking particular chromosomes due to multipolar mitosis promotes clonal evolution in colorectal cancer cells

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Involvement of p38α in the mitotic progression ofp53^-/-tetraploid cells