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Ref Type Journal Article
PMID (22438244)
Authors Jemaa M, Vitale I, Kepp O, Berardinelli F, Galluzzi L, Senovilla L, Marino G, Malik SA, Rello-Varona S, Lissa D, Antoccia A, Tailler M, Schlemmer F, Harper F, Pierron G, Castedo M, Kroemer G
Title Selective killing of p53-deficient cancer cells by SP600125.
Journal Vol Issue Date Pages Journal Short Title
EMBO molecular medicine 4 6 2012 Jun 500-14 EMBO Mol Med
URL
Abstract Text 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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