Selective killing of p53‐deficient cancer cells by SP600125

EMBO Molecular Medicine

Mohamed Jema๠ 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 】

Abstract

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.

【 授权许可】

Unknown   
Copyright © 2012 EMBO Molecular Medicine