Selective resistance of tetraploid cancer cells against DNA damage-induced apoptosis

Maria Castedo, Arnaud Coquelle, Ilio Vitale, Sonia Vivet, Shahul Mouhamad, Sophie Viaud, Laurence Zitvogel, Guido Kroemer

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract

Aneuploidy and chromosomal instability,which are frequent in cancer, can result from the asymmetric division of tetraploid precursors. Genomic instability may favor the generation of more aggressive tumor cells with a reduced propensity for undergoing apoptosis. To assess the impact of tetraploidization on apoptosis regulation, we generated a series of stable tetraploid HCT116 and RKO colon carcinoma cell lines. When comparing diploid parental cells with tetraploid clones, we found that such cells were equally sensitive to a series of cytotoxic agents (staurosporine [STS], hydroxyurea, etoposide), as well as to the lysis by natural killer cells. In strict contrast, tetraploid cells were found to be relatively resistant against a series of DNA-damaging agents, namely cisplatin, oxaliplatin, camptothecin, and γ- and UVC-irradiation. This increased resistance correlated with a reduced manifestation of apoptotic parameters (such as the dissipation of the mitochondrial transmembrane potential and the degradation of nuclear DNA) in tetraploid as compared to diploid cells subjected to DNA damage. Moreover, tetraploid cells manifested an enhanced baseline level of p53 activation. Inhibition of p53 abolished the difference in the susceptibility of diploid and tetraploid cancer cells to DNA damage-induced apoptosis. These data point to an intrinsic resistance of tetraploid cells against radiotherapy and DNA-targeted chemotherapy that may be linked to the status of the p53 system.

Original languageEnglish
Title of host publicationAnnals of the New York Academy of Sciences
Pages35-49
Number of pages15
Volume1090
DOIs
Publication statusPublished - Dec 2006

Publication series

NameAnnals of the New York Academy of Sciences
Volume1090
ISSN (Print)00778923
ISSN (Electronic)17496632

Keywords

  • Cell death
  • Chemoresistance
  • Irradiation
  • p53

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Castedo, M., Coquelle, A., Vitale, I., Vivet, S., Mouhamad, S., Viaud, S., Zitvogel, L., & Kroemer, G. (2006). Selective resistance of tetraploid cancer cells against DNA damage-induced apoptosis. In Annals of the New York Academy of Sciences (Vol. 1090, pp. 35-49). (Annals of the New York Academy of Sciences; Vol. 1090). https://doi.org/10.1196/annals.1378.004