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[Cancer Research 65, 203-209, January 1, 2005]
© 2005 American Association for Cancer Research

Cell and Tumor Biology

A Mutation in the SDHC Gene of Complex II Increases Oxidative Stress, Resulting in Apoptosis and Tumorigenesis

Takamasa Ishii1, Kayo Yasuda1, Akira Akatsuka2, Okio Hino3, Philip S. Hartman4 and Naoaki Ishii1

1 Department of Molecular Life Science and 2 Teaching and Research Support Center, Tokai University School of Medicine, Kanagawa, Japan; 3 Department of Experimental Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan; and 4 Department of Biology, Texas Christian University, Fort Worth, Texas

Requests for reprints: Naoaki Ishii, Department of Molecular Life Science, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan. Phone: 463-93-1121 ext. 2650; Fax: 463-94-8884. E-mail: nishii{at}is.icc.u-tokai.ac.jp.

Intracellular oxidative stress from mitochondria is thought to be important in carcinogenesis and tumorigenesis, but direct experimental proof is limited. In this study, a transgenic mouse cell line (SDHC E69) with a mutated SDHC gene (a subunit of complex II in the electron transport chain) was constructed to test this question. The SDHC E69 cells overproduced superoxide anion (O2–) from mitochondria, had elevated cytoplasmic carbonyl proteins and 8-OH-deoxyguanine in their DNA as well as significantly higher mutation frequencies than wild type. There were many apoptotic cells in this cell line, as predicted by the observed increase in caspase 3 activity, decrease in mitochondrial membrane potential, and structural changes in their mitochondria. In addition, some cells that escaped from apoptosis underwent transformation, as evidenced by the fact that SDHC E69 cells caused benign tumors when injected under the epithelium of nude mice. These results underscore the notion that mitochondrially generated oxidative stress can contribute to nuclear DNA damage, mutagenesis, and ultimately, tumorigenesis.

Key Words: oxidative stress • apoptosis • mitochondria • mutation • paraganglioma • 01-01-12 reactive oxygen and carcinogenesis • 02-03-00 cell death and senescence • 11-01-03 DNA damage, DNA repair, mutagenesis • 02-00-00 CELLULAR, MOLECULAR, AND TUMOR BIOLOGY




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