Two distinct modes of cell death induced by doxorubicin: apoptosis and cell death through mitotic catastrophe accompanied by senescence-like phenotype.
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.
Eom
Young-Woo
YW
Laboratory of Endocrinology, Ajou University School of Medicine, San 5, Wonchon-Dong, Youngtong-Gu, Suwon 442-749, South Korea.
Kim
Mi Ae
MA
Park
Seok Soon
SS
Goo
Mi Jin
MJ
Kwon
Hyuk Jae
HJ
Sohn
Seonghyang
S
Kim
Wook-Hwan
WH
Yoon
Gyesoon
G
Choi
Kyeong Sook
KS
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects*; D045304:Cytochromes c / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D034921:Lamin Type B / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D008941:Spindle Apparatus / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D034921:Lamin Type B; D016328:NF-kappa B; D004317:Doxorubicin; D045304:Cytochromes c; D004247:DNA; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases