Apoptosis regulation in tetraploid cancer cells

Abstract

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

Caspase independence of radio-induced cell death

“…Moreover, Z-VAD-fmk reduced the frequency of dying (Annexin V þ PI -) or dead (Annexin V þ PI þ ) cells, irrespective of the genotype of the cells that were g-irradiated ( Figure 6d). As a further proof that caspase inhibition has a significant phenotypic impact on g-irradiation-induced cell death, we found that Z-VAD-fmk increased the percentage of cells containing multiple nuclei (Figure 7a and b) with a consequent polyploid DNA content (>4N, Figure 7c) induced by g-irradiation, in accord with the previously reported observation that polyploid cells succumb to caspase activation (Ferri et al, 2000;Castedo et al, 2006). Altogether, these data indicate that apoptosis induced by g-irradiation, as defined by chromatin condensation, DNA loss and Annexin V-positivity, is efficiently inhibited by Z-VAD-fmk.…”

MOS, aneuploidy and the ploidy cycle of cancer cells

“…Kondrashov (1994Kondrashov ( , 1997 also showed that the ploidy cycle has the advantage of decreasing the mutational load as compared with permanent diploidy or permanent polyploidy and therefore should appear in evolutionary development when this property is required. Among other advantages, polyploidy provides tumor cells with durability against genotoxic damage (Castedo et al, 2006;Lee et al, 2009) and, indeed, reversible polyploidy seems to be operating during the response to it Sundaram et al, 2004;Puig et al, 2008).…”

“…A key molecular regulator of this phenomenon is p53, whose deficiency is permissive for the bypass of mitotic catastrophe and the creation and survival of tetraploid cells, a metastable intermediate between normal diploidy and oncogenic aneuploidy (Storchova and Pellman, 2004;Castedo et al, 2004Castedo et al, , 2006Ganem and Pellman, 2007;Thompson and Compton, 2010).…”

Deregulation of Cdk2 causes Bim-mediated apoptosis in p53-deficient tumors following actin damage

“…Cells with overexpression of Bcl-x L have an increased rate of spontaneous tetraploidization (Minn et al, 1996;Castedo et al, 2006), suggesting that apoptosis may play an important role in eliminating cells that fail to complete mitosis properly. We showed that Bcl-x L suppressed the apoptosis of p53-deficient cells by PTX-2.…”