Mitotic Catastrophe Results in Cell Death by Caspase-Dependentand Caspase-Independent Mechanisms

Abstract

Exposure of MDA-MB-231 and MCF-7/VP human breast carcinoma cells to the anthracyclines doxorubicin and WP631 induced polyploidy, formation of multinucleated cells and cell death by mitotic catastrophe through caspase-dependent and caspase-independent mechanisms. In both cell lines, the antiproliferative effect of WP631 was higher than that of doxorubicin and a transient halt in G(2)/M was observed without cell senescence, while p53-dependent apoptosis did not occur in these cells. Mitotic catastrophe was linked to necrosis, but also to apoptosis-like death, estimated by differential cell staining with annexin-V-fluorescein and propidium iodide. Drug-induced changes in the expression of c-myc and p21(WAF1), and in their respective protein levels, were observed. They depended on the cell line, the anthracycline used and its concentration, and they were consistent with the cell cycle progression through G(2) to mitosis. Significant activation of caspase-2 and caspase-3 was only observed in MDA-MB-231 cells treated with doxorubicin but not with WP631, indicating that caspases may be not mandatory for the occurrence of cell death through mitotic catastrophe. In MCF-7/VP cells, which do not express functional caspase-3, mitotic catastrophe was also induced.

Molecular profiling of docetaxel cytotoxicity in breast cancer cells: uncoupling of aberrant mitosis and apoptosis

“…Interestingly, although longer time points would be necessary to evaluate the final effect of different concentrations of docetaxel in breast cancer cells, long-term assays show that cells undergoing mitotic catastrophe eventually result in cell death, reducing overall clonogenic survival (Roninson et al, 2001;Blagosklonny et al, 2002). Moreover, in agreement with several studies, mitotic death normally ends in necrosis (Mansilla et al, 2006).…”

Caspase-2 as a tumour suppressor

“…19 In line with these findings, caspase-2 has also been implicated in a mode of cell death that is induced following aberrant mitoses called mitotic catastrophe. 42,43 Despite the lack of a clear molecular definition for mitotic catastrophe, it has been proposed to be important for the deletion of aneuploid cells generated from abnormal mitotic events. 44 Therefore, mitotic catastrophe has been viewed as a tumour-suppressive process that is important for maintaining genomic stability.…”

A nuclear budding mechanism in transiently arrested cells generates drug-sensitive and drug-resistant cells

“…Apoptosis protects cells from aneuploidy [1,6], but tumor cells usually have defective apoptotic pathways, thus they may enter mitosis that is prolonged for extended periods of time, or the cells may be committed to dying by mitotic catastrophe, which can be induced by caspasedependent or caspase-independent mechanisms [7]. Moreover, some cells can overcome such a defective mitosis but they are halted in the ensuring G1 phase; an arrest that is considered to be p53-dependent [8,9].…”

“…Several DNA-binding drugs have been reported to produce mitotic catastrophe in both cells containing wild-type p53 and those bearing mutated or deleted p53 genes [13][14][15][16][17]. Mitotic catastrophe occurs in tumor cells treated with various antitumour drugs or radiation [7,13,14,[16][17][18][19][20][21]. These antitumour agents can also limit tumor growth through accelerated senescence arrest [10,12,13,22].…”

“…Senescence may also follow mitotic catastrophe if polyploid cells are arrested in G1 or G2 after mitotic catastrophe [13,24], but the arrest is not permanent when, for example, cells lack p53 function, or the p53 and p21 WAF1 protein levels decrease after treatment with certain drugs [7,11,13,21,22,25], or as a result of alterations in the phosphorilation of Chk1 [19]. Therefore, cells can re-enter the cell cycle, increasing their polyploidy before they eventually die.…”