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- Title
Two distinct modes of cell death induced by doxorubicin: apoptosis and cell death through mitotic catastrophe accompanied by senescence-like phenotype.
- Authors
Eom, Young-Woo; Kim, Mi Ae; Park, Seok Soon; Goo, Mi Jin; Kwon, Hyuk Jae; Sohn, Seonghyang; Kim, Wook-Hwan; Yoon, Gyesoon; Choi, Kyeong Sook
- Abstract
Chronic exposure of many human hepatoma cell lines to a low dose (LD) of doxorubicin induced a senescence-like phenotype (SLP) accompanied by enlargement of cells and increased senescence-associated β-galactosidase activity. LD doxorubicin-induced SLP was preceded by multinucleation and downregulation of multiple proteins with mitotic checkpoint function, including CENP-A, Mad2, BubR1, and Chk1. LD doxorubicin-treated cells eventually underwent cell death through mitotic catastrophe. When we investigated whether LD doxorubicin-induced cell death shares biochemical characteristics with high dose (HD) doxorubicin-induced apoptosis in Huh-7 cells, we observed that externalization of phosphatidyl serine and release of mitochondrial cytochrome c into the cytosol was associated with both types of cell death. However, propidium iodide exclusion assays showed that membrane integrity was lost in the initial phase of LD doxorubicin-induced cell death through mitotic catastrophe, whereas it was lost during the late phase of HD doxorubicin-induced apoptosis. Furthermore, HD doxorubicin-induced apoptosis but not LD doxorubicin-induced mitotic catastrophe led to transient activation of NF-κB and strong, sustained activations of p38, c-Jun N-terminal kinase, and caspases. Collectively, these results indicate that different doses of doxorubicin activate different regulatory mechanisms to induce either apoptosis or cell death through mitotic catastrophe.Oncogene (2005) 24, 4765–4777. doi:10.1038/sj.onc.1208627; published online 2 May 2005
- Subjects
CELL death; ANTHRACYCLINES; APOPTOSIS; CYTOCHROME c; CYTOSOL; MITOSIS
- Publication
Oncogene, 2005, Vol 24, Issue 30, p4765
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1208627