Selective killing of p53-deficient cancer cells by SP600125

Mohamed Jemaà, Ilio Vitale, Oliver Kepp, Francesco Berardinelli, Lorenzo Galluzzi, Laura Senovilla, Guillermo Mariño, Shoaib Ahmad Malik, Santiago Rello-Varona, Delphine Lissa, Antonio Antoccia, Maximilien Tailler, Frederic Schlemmer, Francis Harper, Gérard Pierron, Maria Castedo, Guido Kroemer

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)500-514
Number of pages15
JournalEMBO Molecular Medicine
Volume4
Issue number6
DOIs
Publication statusPublished - Jun 2012

Keywords

  • Caspases
  • HCT 116
  • High-throughput screening
  • Mitochondrial outer membrane permeabilization
  • MPS1

ASJC Scopus subject areas

  • Molecular Medicine

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