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Cytotoxic amounts of cisplatin induce either checkpoint adaptation or apoptosis in a concentration‐dependent manner in cancer cells
Author(s) -
Swift Lucy H.,
Golsteyn Roy M.
Publication year - 2016
Publication title -
biology of the cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 85
eISSN - 1768-322X
pISSN - 0248-4900
DOI - 10.1111/boc.201500056
Subject(s) - biology , cisplatin , cytotoxic t cell , apoptosis , adaptation (eye) , cancer , cancer research , cancer cell , microbiology and biotechnology , biochemistry , genetics , in vitro , neuroscience , chemotherapy
Background Information Checkpoint adaptation (entry into mitosis with damaged DNA) is a process that links arrest at the G2/M cell cycle checkpoint and cell death in cancer cells. It is not known, however, whether cells treated with the genotoxic agent, cisplatin, undergo checkpoint adaptation or if checkpoint adaptation is a major pathway leading to cell death or not. Therefore, we investigated the relationship between treatment with cisplatin and cytotoxicity in cancer cells. Results Treatment of HT‐29 human colorectal adenocarcinoma cells with cisplatin can induce cell death by one of two different mechanisms. Cells treated with a cytotoxic 30 μM amount of cisplatin died after undergoing checkpoint adaptation. Before dying, however, almost all treated cells were positive for histone γH2AX staining and contained high levels of cyclin B1. Rounded cells appeared that were positive for phospho‐Ser10 histone H3, with low levels of phospho‐Tyr15 cyclin‐dependent kinase 1, high levels of cyclin‐dependent kinase 1 activity, and checkpoint kinase 1 that was not phosphorylated on Ser345. These cells were in mitosis with damaged DNA. Strikingly, with 30 μM cisplatin, 81% of cells had entered mitosis before dying. By contrast, after treatment with 100 μM cisplatin, nearly all cells died but only 7% of cells had entered mitosis. Instead, these cells died by apoptosis; they were positive for annexin‐V staining, contained cleaved caspase 3, cleaved caspase 9 and cleaved PARP and did not contain Mcl‐1. Conclusions Our data demonstrate that cancer cells treated with cisplatin can undergo one of two modes of cell death depending upon concentration used. These findings suggest that checkpoint adaptation is likely a primary pathway in genotoxic cell death at pharmacological concentrations of cisplatin. Significance Checkpoint adaptation might be a common biochemical pathway taken by human cancer cells in response to pharmacologically relevant, cytotoxic amounts of damaged DNA.