DNA damage induces two distinct modes of cell death in ovarian carcinomas

Abstract

Activation of p53 by cellular stress may lead to either cell cycle arrest or apoptotic cell death. Restrictions in a cell's ability to halt the cell cycle might, in turn, cause mitotic catastrophe, a delayed type of cell death with distinct morphological features. Here, we have investigated the contribution of p53 and caspase-2 to apoptotic cell death and mitotic catastrophe in cisplatin-treated ovarian carcinoma cell lines. We report that both functional p53 and caspase-2 were required for the apoptotic response, which was preceded by translocation of nuclear caspase-2 to the cytoplasm. In the absence of functional p53, cisplatin treatment resulted in caspase-2-independent mitotic catastrophe followed by necrosis. In these cells, apoptotic functions could be restored by transient expression of wt p53. Hence, p53 appeared to act as a switch between apoptosis and mitotic catastrophe followed by necrosis-like lysis in this experimental model. Further, we show that inhibition of Chk2, and/or 14-3-3r deficiency, sensitized cells to undergo mitotic catastrophe upon treatment with DNA-damaging agents. However, apoptotic cell death seemed to be the final outcome of this process. Thus, we hypothesize that the final mode of cell death triggered by DNA damage in ovarian carcinoma cells is determined by the profile of proteins involved in the regulation of the cell cycle, such as p53-and Chk2-related proteins.

Opposing effects of hMOF and SIRT1 on H4K16 acetylation and the sensitivity to the topoisomerase II inhibitor etoposide

“…Whereas TSA promoted VP16-induced apoptotic cell death, VPA/VP16 co-treatment induced nuclear morphology resembling mitotic catastrophe (Figure 1b), an event associated with block in mitosis, mitotic spindle disorganization, failed chromosome segregation and formation of multinucleated cells (Castedo et al, 2004). Later on these cells died by necrosis-like lysis (Vakifahmetoglu et al, 2008). The promoting effect of TSA and VPA treatment on VP16-induced cell death was further investigated and confirmed by clonogenic assay at 10 days (Figures 2a-c).…”

Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

“…8 However, apoptotic and necrotic traits have also been detected in such cells, either concomitant with or following multinucleation. 109,110 Thus, end-point techniques are intrinsically unsuitable for assessing mitotic catastrophe, as they cannot reconstruct the sequence of events that have lead to cell death. To circumvent this issue, novel methods relying on high-throughput video microscopy or time-lapse fluorescence microscopy are under development.…”

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

“…One interesting example is the proposed regulation of the final mode of cell death triggered by DNA damage in ovarian carcinoma cells. Vakifahmetoglu et al (2008a) reported that molecular profiles involving caspase-2, Chk2 as well as p53 not only determine whether cells undergo cell cycle regulation, necrosis, apoptosis or mitotic catastrophe but also determine whether cells undergo apoptosis or necrosis following mitotic catastrophe. More effective therapy for refractory malignancies has been investigated using small-molecule inhibitors to target key proteins in the intrinsic apoptotic pathway (Goldsmith et al, 2006;Gudiksen et al, 2008).…”