Carcinogenesis Advance Access published online on March 26, 2007
Carcinogenesis, doi:10.1093/carcin/bgm072
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Targeting Human 8-Oxoguanine DNA Glycosylase (hOGG1) to Mitochondria Enhances Cisplatin Cytotoxicity in Hepatoma Cells
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* From the Department of Pathology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205
From the Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205
From the Department of Biostatistics, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205
¶ From the Department of Otolaryngology-Head and Neck Surgery, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205
John L. McClellan Memorial Veterans Hospital, 4300 West 7th Street, Little Rock, AR 72205
# Division of Carcinogenesis, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Withington, Manchester M20 4BX, United Kingdom
Correspondence to: Chun-Yang Fan, M.D., Ph.D., Department of Pathology (LR/113), University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, 4300 West 7th Street, Little Rock, AR 72205; Phone: 501 257-6469, Fax: 501 257-6430; email: fanchunyang{at}uams.edu
Many chemoradiation therapies cause DNA damage through oxidative stress. An important cellular mechanism that protects cells against oxidative stress involves DNA repair. One of the primary DNA repair mechanisms for oxidative DNA damage is base excision repair (BER). BER involves the tightly coordinated function of four enzymes (glycosylase, AP endonuclease, polymerase, ligase), in which 8-oxoguanine DNA glycosylase 1 (OGG1) initiates the cycle. An imbalance in the production of any one of these enzymes may result in the generation of more DNA damage and increased cell killing. In this study, we targeted mitochondrial DNA to enhance cancer chemotherapy by overexpressing a human OGG1 (hOGG1) gene in the mitochondria of human hepatoma cells. Increased hOGG1 transgene expression was achieved at RNA, protein, and enzyme activity levels. In parallel, we observed enhanced mitochondrial DNA damage, increased mitochondrial respiration rate, increased membrane potential, and elevated free radical production. A greater proportion of the hOGG1-overexpressing hepatoma cells experienced apoptosis. Following exposure to a commonly used chemotherapeutic agent, cisplatin, cancer cells overexpressing hOGG1 displayed much shortened long-term survival when compared to control cells. Our results suggest that overexpression of hOGG1 in mitochondria may promote mitochondrial DNA damage by creating an imbalance in the BER pathway and sensitize cancer cells to cisplatin. These findings support further evaluation of hOGG1 overexpression strategies for cancer therapy.
Key Words: hOGG1 • imbalanced base excision repair • mitochondria • free radical • chemotherapy
¥ These two authors contributed equally to the manuscript.
Received January 28, 2007; revised March 1, 2007; accepted March 19, 2007.
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