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  • The EMBO Journal (2006) 25, 2584 - 2595
  • doi:10.1038/sj.emboj.7601127

Published online: 4 May 2006

Apoptosis regulation in tetraploid cancer cells

Maria Castedo1,a, Arnaud Coquelle1,a, Sonia Vivet1, Ilio Vitale1, Audrey Kauffmann1, Philippe Dessen1, Marie O Pequignot1, Noelia Casares1, Alexandre Valent2, Shahul Mouhamad1, Elise Schmitt3, Nazanine Modjtahedi1, William Vainchenker4, Laurence Zitvogel5, Vladimir Lazar2, Carmen Garrido3 and Guido Kroemer1

  1. CNRS, UMR8125, Institut Gustave Roussy, Villejuif, France
  2. Unité de Génomique Fonctionnelle, Institut Gustave Roussy, Villejuif, France
  3. INSERM U-517, Faculty of Medicine and Pharmacy, Dijon, France
  4. INSERM U362, Institut Gustave Roussy, Villejuif, France
  5. INSERM ERM0208, Institut Gustave Roussy, Villejuif, France

Correspondence to:

Guido Kroemer, CNRS-UMR8125, Institut Gustave Roussy, PR1, 39 rue Camille Desmoulins, 94805 Villejuif, France. Tel.: +33 1 42 11 60 46; Fax: +33 1 42 11 60 47; E-mail: kroemer@igr.fr

aThese authors contributed equally to this work

Received 30 September 2005; Accepted 11 April 2006

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 gamma-irradiation. These data indicate the existence of p53-dependent alterations in apoptosis regulation in tetraploid cells.

  • Keywords:

    • apoptosis,
    • bax,
    • chemoresistance,
    • mitochondria,
    • p53