title: Selective resistance of tetraploid cancer cells against DNA damage-induced apoptosis.
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 gamma- 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.
authors: Centre National de la Recherche Scientifique, UMR8125, Villejuif, France.
authors: Maria
authors: M
authors: Castedo
authors: Arnaud
authors: A
authors: Coquelle
authors: Ilio
authors: I
authors: Vitale
authors: Sonia
authors: S
authors: Vivet
authors: Shahul
authors: S
authors: Mouhamad
authors: Sophie
authors: S
authors: Viaud
authors: Laurence
authors: L
authors: Zitvogel
authors: Guido
authors: G
authors: Kroemer
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology*; D004249:DNA Damage; D005455:Fluorescent Antibody Technique; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D011123:Polyploidy; D014466:Ultraviolet Rays
chemical_list: D000970:Antineoplastic Agents