Apoptosis regulation in tetraploid cancer cells

Maria Castedo, Arnaud Coquelle, Sonia Vivet, Ilio Vitale, Audrey Kauffmann, Philippe Dessen, Marie O. Pequignot, Noelia Casares, Alexandre Valent, Shahul Mouhamad, Elise Schmitt, Nazanine Modjtahedi, William Vainchenker, Laurence Zitvogel, Vladimir Lazar, Carmen Garrido, Guido Kroemer

    Research output: Contribution to journalArticlepeer-review

    172 Citations (Scopus)

    Abstract

    Tetraploidy can result in cancer-associated aneuploidy. As shown here, freshly generated tetraploid cells arising due to mitotic slippage or failed cytokinesis are prone to undergo Bax-dependent mitochondrial membrane permeabilization and subsequent apoptosis. Knockout of Bax or overexpression of Bcl-2 facilitated the survival of tetraploid cells at least as efficiently as the p53 or p21 knockout. When tetraploid cells were derived from diploid p53 and Bax-proficient precursors, such cells exhibited an enhanced transcription of p53 target genes. Tetraploid cells exhibited an enhanced rate of spontaneous apoptosis that could be suppressed by inhibition of p53 or by knockdown of proapoptotic p53 target genes such as BBC3/Puma, GADD45A and ferredoxin reductase. Unexpectedly, tetraploid cells were more resistant to DNA damaging agents (cisplatin, oxaliplatin and camptothecin) than their diploid counterparts, and this difference disappeared upon inhibition of p53 or knockdown of p53-inducible ribonucleotide reductase. Tetraploid cells were also more resistant against UVC and γ-irradiation. These data indicate the existence of p53-dependent alterations in apoptosis regulation in tetraploid cells.

    Original languageEnglish
    Pages (from-to)2584-2595
    Number of pages12
    JournalEMBO Journal
    Volume25
    Issue number11
    DOIs
    Publication statusPublished - 7 Jul 2006

    Keywords

    • Apoptosis
    • Bax
    • Chemoresistance
    • Mitochondria
    • p53

    Cite this