Targeting human 8-oxoguanine DNA glycosylase (hOGG1) to mitochondria enhances cisplatin cytotoxicity in hepatoma cells.
Targeting human 8-oxoguanine DNA glycosylase (hOGG1) to mitochondria enhances cisplatin cytotoxicity in hepatoma cells.
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DOI：
10.1093/carcin/bgm072
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发表时间：
2007-08
期刊：
影响因子：
4.7
通讯作者：
Haihong Zhang;T. Mizumachi;J. Cárcel-Trullols;Liwen Li;A. Naito;H. Spencer;P. Spring;B. Smoller-B.-Smol
中科院分区：
文献类型：
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作者：
Haihong Zhang;T. Mizumachi;J. Cárcel-Trullols;Liwen Li;A. Naito;H. Spencer;P. Spring;B. Smoller-B.-Smol
许多放化疗疗法通过氧化应激引起DNA损伤。保护细胞免受氧化应激的重要细胞机制涉及DNA修复。DNA氧化损伤的主要修复机制之一是碱基切除修复（BER）。BER涉及四种酶（糖基化酶、脱嘌呤/脱嘧啶核酸内切酶、聚合酶和连接酶）的紧密协调功能，其中8-氧代鸟嘌呤DNA糖基化酶1启动循环。任何一种酶的生产不平衡都可能导致更多的DNA损伤和细胞杀伤增加。在这项研究中，我们通过在人肝癌细胞的线粒体中过表达人8-氧代鸟嘌呤DNA糖基化酶1（hOGG 1）基因来靶向线粒体DNA以增强癌症化疗。在RNA、蛋白质和酶活性水平上实现了hOGG 1转基因表达的增加。同时，我们观察到线粒体DNA损伤增强，线粒体呼吸速率增加，膜电位增加和自由基产生增加。更大比例的hOGG 1过表达肝癌细胞经历了凋亡。在暴露于常用的化疗剂顺铂后，与对照细胞相比，过表达hOGG 1的癌细胞显示出更短的长期存活。我们的研究结果表明，hOGG 1在线粒体中的过度表达可能会促进线粒体DNA损伤，通过在BER途径中产生不平衡，并使癌细胞对顺铂敏感。这些发现支持进一步评估hOGG 1过表达策略用于癌症治疗。
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, apurinic/apyrimidinic endonuclease, polymerase and ligase), in which 8-oxoguanine DNA glycosylase 1 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 over-expressing a human 8-oxoguanine DNA glycosylase 1 (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-over-expressing hepatoma cells experienced apoptosis. Following exposure to a commonly used chemotherapeutic agent, cisplatin, cancer cells over-expressing hOGG1 displayed much shortened long-term survival when compared with control cells. Our results suggest that over-expression 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 over-expression strategies for cancer therapy.