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Two distinct modes of cell death induced by doxorubicin: apoptosis and cell death through mitotic catastrophe accompanied by senescence-like phenotype.

Authors
Eom, YW; Kim, MA; Park, SS; Goo, MJ; Kwon, HJ; Sohn, S; Kim, WH; Yoon, G; Choi, KS
Citation
Oncogene, 24(30):4765-4777, 2005
Journal Title
Oncogene
ISSN
0950-92321476-5594
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 beta-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-kappaB 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.
MeSH terms
Apoptosis/drug effects*Caspases/metabolismCell Aging/drug effects*Cell Death/drug effectsCell Line, TumorCell Membrane Permeability/drug effectsCell Nucleus/drug effectsCell Nucleus/metabolismCytochromes c/metabolismDNA/metabolismDown-RegulationDoxorubicin/pharmacology*Enzyme Activation/drug effectsHumansKineticsLamin Type B/metabolismMicroscopy, Electron, TransmissionMitochondria/metabolismMitosis/drug effects*Mitotic Spindle Apparatus/drug effectsModels, BiologicalNF-kappa B/metabolismPhenotypeSignal Transduction/drug effectsp38 Mitogen-Activated Protein Kinases/metabolism
DOI
10.1038/sj.onc.1208627
PMID
15870702
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Microbiology
Journal Papers > School of Medicine / Graduate School of Medicine > Surgery
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
AJOU Authors
손, 성향김, 욱환윤, 계순최, 경숙
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