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  • Original Paper
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Resistance of mitochondrial DNA-deficient cells to TRAIL: role of Bax in TRAIL-induced apoptosis

Oncogene volume 21, pages 3139–3148 (2002)Cite this article

Abstract

Mitochondrion is one of the master players in both apoptosis and necrosis. We studied the role of mitochondrial function in TRAIL-induced apoptosis. TRAIL killed SK-Hep1 cells with characteristic features of apoptosis such as DNA fragmentation, sub-G1 ploidy peak and cytochrome c translocation. In contrast, mitochondrial DNA-deficient SK-Hep1 ρ0 cells were resistant to TRAIL. Dissipation of mitochondrial potential or cytochrome c translocation did not occur in ρ0 cells after TRAIL treatment. TRAIL induced translocation of Bax subsequent to the cleavage of Bid in parental cells. However, Bax translocation was absent in ρ0 cells, accounting for the failure of cytochrome c release in ρ0 cells. Forced expression of Bax induced caspase-3 activity in ρ0 cells. Incubation of ρ0 cells with ADP+Pi to increase intracellular ATP restored sensitivity to TRAIL. Despite different sensitivity to TRAIL, parental cells and ρ0 cells did not show significant difference in susceptibility to agonistic anti-Fas antibody, TNF-α or staurosporine. Our results indicate that TRAIL-induced apoptosis is dependent on intact mitochondrial function and susceptibility of mitochondrial DNA-deficient cells to apoptosis depends on the type of apoptotic stimuli. Tumor cells with mitochondrial mutations or dysfunction might have the ability to evade tumor surveillance imposed by TRAIL in vivo.

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Acknowledgements

The authors thank Drs K Suk, H-Y Park and P-G Suh for helpful discussion. This work was supported by the National Research Laboratory Grants from the Korea Institute of Science and Technology Evaluation and Planning (2000-N-NL-01-C-232), and Science Research Center Grants from Korea Science and Engineering Foundation. M-S Lee is an awardee of the Juvenile Diabetes Foundation International Research Grant (1-1999-760).

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Authors and Affiliations

  1. Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Kangnam-ku, Seoul, 135-710, Korea

    Ja-Young Kim, Yun-Hee Kim, Inik Chang, Sunshin Kim & Myung-Shik Lee

  2. Department of Life Science, Pohang University of Science and Technology, Pohang, 790-784, Kyungbuk, Korea

    Yun-Hee Kim & Byung-Ha Oh

  3. Division of Metabolic Disease, Department of Biomedical Sciences, National Institute of Health, 5 Nokbun-dong Eunpyung-ku, Seoul, 122-710, Korea

    Youngmi Kim Pak

  4. Department of Immunology, Juntendo University School of Medicine, Tokyo, 113-8421, Japan

    Hideo Yagita

  5. Department of Life Science, Kwangju Institute of Science and Technology, Puk-gu, Kwangju, 500-712, Korea

    Yong Keun Jung

  6. Department of Biology, Yonsei University College of Science, Seoul, 120-749, Korea

    Young Joon Oh

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Kim, JY., Kim, YH., Chang, I. et al. Resistance of mitochondrial DNA-deficient cells to TRAIL: role of Bax in TRAIL-induced apoptosis. Oncogene 21, 3139–3148 (2002). https://doi.org/10.1038/sj.onc.1205406

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