Apoptosis regulation in tetraploid cancer cells

• Published in: The EMBO journal Vol. 25; no. 11; pp. 2584 - 2595
• Main Authors: Castedo, Maria, Coquelle, Arnaud, Vivet, Sonia, Vitale, Ilio, Kauffmann, Audrey, Dessen, Philippe, Pequignot, Marie O, Casares, Noelia, Valent, Alexandre, Mouhamad, Shahul, Schmitt, Elise, Modjtahedi, Nazanine, Vainchenker, William, Zitvogel, Laurence, Lazar, Vladimir, Garrido, Carmen, Kroemer, Guido
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 07.06.2006; Blackwell Publishing Ltd; EMBO Press
• Subjects: Animals; Antineoplastic Agents - metabolism; Apoptosis; Apoptosis - physiology; bax; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Biomedical research; Cell Line, Tumor; chemoresistance; Cisplatin - metabolism; Cross-Linking Reagents - metabolism; Deoxyribonucleic acid; DNA; DNA Damage; Female; Gamma rays; Gene Deletion; Humans; Irradiation; Life Sciences; Mice; Mice, Nude; mitochondria; Molecular biology; Neoplasms - genetics; Neoplasms - metabolism; Nocodazole - metabolism; Oligonucleotide Array Sequence Analysis; Oncology; p53; Polyploidy; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Transcription, Genetic; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Ultraviolet radiation
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/sj.emboj.7601127

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.