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Apoptosis regulation in tetraploid cancer cells
Author(s) -
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
Publication year - 2006
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601127
Subject(s) - biology , gene knockdown , apoptosis , cancer cell , camptothecin , mitotic catastrophe , dna damage , ribonucleotide reductase , microbiology and biotechnology , mitosis , cancer research , programmed cell death , gene , genetics , dna , cancer , biochemistry , protein subunit
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.