EMBO Molecular Medicine | |
Selective killing of p53‐deficient cancer cells by SP600125 | |
Mohamed Jemaà1  Ilio Vitale1  Oliver Kepp1  Francesco Berardinelli3  Lorenzo Galluzzi1  Laura Senovilla1  Guillermo Mariño1  Shoaib Ahmad Malik1  Santiago Rello-Varona1  Delphine Lissa1  Antonio Antoccia3  Maximilien Tailler1  Frederic Schlemmer1  Francis Harper2  Gérard Pierron2  Maria Castedo1  | |
[1] INSERM, U848, Villejuif, France;CNRS, UMR8122, Villejuif, France;Dipartimento Di Biologia, Università Roma Tre, Rome, Italy | |
关键词: caspases; HCT 116; high‐throughput screening; mitochondrial outer membrane permeabilization; MPS1; | |
DOI : 10.1002/emmm.201200228 | |
来源: Wiley | |
【 摘 要 】
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.Abstract
【 授权许可】
Unknown
Copyright © 2012 EMBO Molecular Medicine
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