Enhancement of apoptotic damage of squamous cell carcinoma cells by inhibition of the mitochondrial DNA repairing system
Enhancement of apoptotic damage of squamous cell carcinoma cells by inhibition of the mitochondrial DNA repairing system
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DOI：
10.1111/j.1349-7006.2008.00918.x
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发表时间：
2008-11-01
期刊：
影响因子：
5.7
通讯作者：
Yamamoto, Tetsuya
中科院分区：
文献类型：
--
作者：
Ueta, Eisaku;Sasabe, Eri;Yamamoto, Tetsuya
线粒体DNA（mtDNA）修复系统被认为与癌细胞对抗癌剂的易感性相关。本研究旨在探讨口腔鳞癌细胞对γ射线的敏感性与线粒体DNA修复能力的关系。放射敏感细胞系OSC-2、OSC-3和OSC-6的核DNA和线粒体DNA中8-羟基-2 '-脱氧鸟苷（8-OHdG）和线粒体DNA共同缺失水平均高于放射抵抗细胞系OSC-1、OSC-4和OSC-5。与OSC-2、OSC-3和OSC-6细胞相比，OSC-1、OSC-4和OSC-5细胞具有更高水平的磷酸肌醇-3激酶（PI-3 K）/Akt活性和更强的8-羟基鸟嘌呤DNA糖基化酶（OGG 1）、DNA聚合酶γ（POLG）和线粒体转录因子A（Tfam）表达。通过RNA干扰技术下调这些mtDNA修复相关分子的表达增强了OSC-2和OSC-5细胞对γ射线的敏感性，PI-3 K/Akt信号通路抑制剂下调了Tfam和POLG的表达。这些结果表明，PI-3 K/Akt信号抑制剂和OGG 1下调剂在癌细胞中抑制mtDNA修复能力可能是一种有用的策略，当与电离辐射和化疗药物联合使用时，用于癌症治疗。（Cancer Sci 2008; 99：2230-2237）。
Mitochondrial DNA (mtDNA) repair systems are thought to be associated with the susceptibility of cancer cells to anticancer agents. The present study investigated the relationship between the susceptibility to gamma-rays and the mtDNA repair ability of oral squamous cell carcinoma (OSC) cell lines. The levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and mtDNA common deletion in both nuclear and mitochondrial DNA of OSC-2, OSC-3 and OSC-6 cells (radio-sensitive cell lines) after gamma-ray-irradiation were higher than those of OSC-1, OSC-4 and OSC-5 cells (radio-resistant cell lines). Compared with OSC-2, OSC-3 and OSC-6 cells, OSC-1, OSC-4 and OSC-5 cells had higher levels of activity of phosphoinositide-3 kinase (PI-3K)/Akt and more strongly expressed 8-hydroxyguanine DNA glycosylase (OGG1), DNA polymerase gamma (POLG) and mitochondrial transcription factor A (Tfam). Down-regulation of these mtDNA-repair-associated molecules by the RNA interference technique enhanced the susceptibility of OSC-2 and OSC-5 cells to gamma-rays, and the expression of Tfam and POLG was down-regulated by inhibitors of PI-3K/Akt signaling. These results indicate that the inhibition of mtDNA repair capacity by PI-3K/Akt signal inhibitors and OGG1 down-regulator in cancer cells may be a useful strategy for cancer treatment when combined with ionizing irradiation and chemotherapeutic drugs. (Cancer Sci 2008; 99: 2230-2237).