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J. Biol. Chem., Vol. 279, Issue 9, 7512-7520, February 27, 2004

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Resistance of Mitochondrial DNA-depleted Cells against Cell Death

ROLE OF MITOCHONDRIAL SUPEROXIDE DISMUTASE^*

Sun Young Park, Inik Chang, Ja-Young Kim, Sang Won Kang¶, Se-Ho Park, Keshav Singh||**, and Myung-Shik Lee

From the Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwondong Kangnam-ku, Seoul 135-710, Korea, the Graduate School of Life Science and Biotechnology, Korea University, 5 Anam-dong, Sungbuk-ku, Seoul 136-701, Korea, the ^¶Center for Cell Signaling Research and Division of Molecular Life Sciences, Ewha Womans University, 11-1 Daehyun-dong, Seodaemoonku, Seoul 120-750, Korea, and the ^||Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263

We have shown that mitochondrial DNA-depleted (⁰) SK-Hep1 hepatoma cells are resistant to apoptosis, contrary to previous papers reporting normal apoptotic susceptibility of ⁰ cells. We studied the changes of gene expression in SK-Hep1 ⁰ cells. DNA chip analysis showed that MnSOD expression was profoundly increased in ⁰ cells. contents increased during ⁰ cell derivation but became normalized after establishment of ⁰ phenotypes, suggesting that MnSOD induction is an adaptive process to increased . ⁰ cells were resistant to menadione, paraquat, or doxorubicin, and contents after treatment with them were lower in ⁰ cells compared with parental cells because of MnSOD overexpression. Expression levels and activity of glutathione peroxidases were also increased in ⁰ cells, rendering them resistant to exogenous H₂O₂. ⁰ cells were resistant to p53, and intracellular ROS contents after p53 expression were lower compared with parental cells. Other types of ⁰ cells also showed increased MnSOD expression and resistance against ROS. Heme oxygenase-1 expression was increased in ⁰ cells, and a heme oxygenase-1 inhibitor decreased the induction of MnSOD in ⁰ cells and their resistance against ROS donors. These results indicate that ⁰ cells are resistant to cell death contrary to previous reports and suggest that an adaptive increase in the expression of antioxidant enzymes renders cancer cells or aged cells with frequent mitochondrial DNA mutations to resist against oxidative stress, host anti-cancer surveillance, or chemotherapeutic agents, conferring survival advantage on them.

Received for publication, July 16, 2003 , and in revised form, November 3, 2003.

^* This work was supported in part by grants from the Health Planning Technology & Evaluation Board and Science Research Center Grants from Korea Science & Engineering Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** Supported by National Institutes of Health Grant RO1-097714.

Awardee of the National Research Laboratory Grants from the Korea Institute of Science & Technology Evaluation and Planning 2000-N-NL-01-C-232. To whom correspondence should be addressed: Dept. of Medicine, Samsung Medical Center, 50 Irwon-dong Kangnam-ku, Seoul 135-710, Korea. Tel.: 82-2-3410-3436; Fax: 82-2-3410-0388; E-mail: mslee{at}smc.samsung.co.kr.

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