期刊
EMBO MOLECULAR MEDICINE
卷 4, 期 6, 页码 500-514出版社
WILEY
DOI: 10.1002/emmm.201200228
关键词
caspases; HCT 116; high-throughput screening; mitochondrial outer membrane permeabilization; MPS1
资金
- Ligue Nationale contre le Cancer
- Fondation de France
- Apo-Sys
- Higher Education Commission (HEC) of Pakistan
- Ligue Nationale contre le Cancer (Equipe labellisee)
- Agence Nationale pour la Recherche (ANR)
- European Commission
- Fondation pour la Recherche Medicale (FRM)
- Institut National du Cancer (INCa)
- Canceropole Ile-de-France
- Fondation Bettencourt-Schueller
- LabEx Onco-Immunology
The genetic or functional inactivation of p53 is highly prevalent in human cancers. Using high-content videomicroscopy based on fluorescent TP53+/+ and TP53-/- human colon carcinoma cells, we discovered that SP600125, a broad-spectrum serine/threonine kinase inhibitor, kills p53-deficient cells more efficiently than their p53-proficient counterparts, in vitro. Similar observations were obtained in vivo, in mice carrying p53-deficient and -proficient human xenografts. Such a preferential cytotoxicity could be attributed to the failure of p53-deficient cells to undergo cell cycle arrest in response to SP600125. TP53-/- (but not TP53+/+) cells treated with SP600125 became polyploid upon mitotic abortion and progressively succumbed to mitochondrial apoptosis. The expression of an SP600125-resistant variant of the mitotic kinase MPS1 in TP53-/- cells reduced SP600125-induced polyploidization. Thus, by targeting MPS1, SP600125 triggers a polyploidization program that cannot be sustained by TP53-/- cells, resulting in the activation of mitotic catastrophe, an oncosuppressive mechanism for the eradication of mitosis-incompetent cells.
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