Survival of aneuploid, micronucleated and/or polyploid cells: crosstalk between ploidy control and apoptosis.

Microtubule inhibitors are known to block the cell cycle at M-phase, by damaging the mitotic spindle. However, under certain circumstances, cells can escape these effects and become aneuploid, polyploid and/or micronucleated. It is well known that aneuploidy can have adverse effects on human health such as pregnancy wastage, birth defects and the development of human tumours. The present paper aims at reviewing the data our laboratory has accumulated during the last years about the relation between aneuploidy/polyploidy/presence of micronuclei and the induction of apoptosis in human cells after in vitro exposure to the microtubule inhibitor nocodazole. Exposure to high doses of nocodazole results in polyploidy due to mitotic slippage in the absence of a functional spindle. Depending on their p53-status polyploid cells may eventually arrest, die or continue cycling. In these experimental conditions, our data showed that polyploidy does not constitute a strong apoptotic signal. In case of exposure to low concentrations of nocodazole, microtubule depolymerization is disturbed resulting in a spindle with damaged microtubules. This can give rise to chromosome loss and non-disjunction. Our data showed that in particular micronucleated cells, originating from chromosome loss can be eliminated by apoptosis. In addition, nocodazole-induced apoptosis involves the apical caspase-8 and -9 and the effector caspase-3. We show evidence that caspase-3, in addition to its function in apoptosis, plays a role in the formation of micronuclei.