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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

Oncogene volume 24, pages 4765–4777 (2005)Cite this article

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.

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Abbreviations

PBS:

phosphate-buffered saline

TUNEL:

terminal deoxynucelotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling

SDS–PAGE:

sodium dodecyl sulfate/polyacrylamide gel electorphoresis

MAP:

mitogen-activated protein

JNK:

c-Jun N-terminal kinase

calcein-AM:

calcein-acetoxymethyl ester

Etd-1:

ethidium homodimer-1

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Acknowledgements

This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (HMP-02-PJ1-PG3-20708-0003) and a grant from the KOSEF (R05-2004-000-10740-0) (to KSC).

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Authors and Affiliations

  1. Laboratory of Endocrinology, Ajou University School of Medicine, San 5, Wonchon-Dong, Youngtong-Gu, 442-749, Suwon, South Korea

    Young-Woo Eom, Mi Ae Kim, Seok Soon Park, Mi Jin Goo & Kyeong Sook Choi

  2. Laboratory of Cell Biology, Institute for Medical Sciences, Ajou University School of Medicine, 442-749, Suwon, South Korea

    Hyuk Jae Kwon & Seonghyang Sohn

  3. Department of Surgery, Ajou University School of Medicine, 442-749, Suwon, South Korea

    Wook-Hwan Kim

  4. Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, 442-749, Suwon, South Korea

    Gyesoon Yoon

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Eom, YW., Kim, M., Park, S. et al. Two distinct modes of cell death induced by doxorubicin: apoptosis and cell death through mitotic catastrophe accompanied by senescence-like phenotype. Oncogene 24, 4765–4777 (2005). https://doi.org/10.1038/sj.onc.1208627

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