DNA damage induces two distinct modes of cell death in ovarian carcinomas.
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 14-3-3sigma 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.
Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
H
H
Vakifahmetoglu
M
M
Olsson
C
C
Tamm
N
N
Heidari
S
S
Orrenius
B
B
Zhivotovsky
D021581:Active Transport, Cell Nucleus; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis; D002277:Carcinoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D053143:Caspase 2 / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology; D064447:Checkpoint Kinase 2; D002945:Cisplatin / Q000633:toxicity*; D004249:DNA Damage; D005260:Female; D006801:Humans; D008938:Mitosis; D009336:Necrosis; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; D053143:Caspase 2; D002945:Cisplatin