title: Selective killing of p53-deficient cancer cells by SP600125.
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.
authors.affiliation: INSERM, U848, Villejuif, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Jemaà
authors.forename: Ilio
authors.initials: I
authors.lastname: Vitale
authors.forename: Oliver
authors.initials: O
authors.lastname: Kepp
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardinelli
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Galluzzi
authors.forename: Laura
authors.initials: L
authors.lastname: Senovilla
authors.forename: Guillermo
authors.initials: G
authors.lastname: Mariño
authors.forename: Shoaib Ahmad
authors.initials: SA
authors.lastname: Malik
authors.forename: Santiago
authors.initials: S
authors.lastname: Rello-Varona
authors.forename: Delphine
authors.initials: D
authors.lastname: Lissa
authors.forename: Antonio
authors.initials: A
authors.lastname: Antoccia
authors.forename: Maximilien
authors.initials: M
authors.lastname: Tailler
authors.forename: Frederic
authors.initials: F
authors.lastname: Schlemmer
authors.forename: Francis
authors.initials: F
authors.lastname: Harper
authors.forename: Gérard
authors.initials: G
authors.lastname: Pierron
authors.forename: Maria
authors.initials: M
authors.lastname: Castedo
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D018715:Microscopy, Video / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000873:Anthracenes; D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; C432165:pyrazolanthrone