Reduced mtDNA copy number increases the sensitivity of tumor cells to chemotherapeutic drugs.
Reduced mtDNA copy number increases the sensitivity of tumor cells to chemotherapeutic drugs.
复制标题
线粒体DNA拷贝数减少会增加肿瘤细胞对化疗药物的敏感性。
DOI：
10.1038/cddis.2015.78
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发表时间：
2015-04-02
影响因子：
9
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Mei H;Sun S;Bai Y;Chen Y;Chai R;Li H
许多癌症药物通过激活凋亡途径对细胞有毒。已有研究表明线粒体在哺乳动物细胞凋亡中起关键作用，但线粒体DNA（mtDNA）拷贝数变异在肿瘤细胞凋亡发病机制中的作用尚不清楚。我们使用HEp-2、HNE 2和A549肿瘤细胞系来探讨mtDNA拷贝数变异与细胞凋亡的关系。我们首先用顺铂（DDP）或阿霉素（DOX）诱导三种肿瘤细胞系和一种正常成人皮肤成纤维细胞系（HSF）的凋亡，发现凋亡肿瘤细胞的mtDNA拷贝数显著增加，而HSF细胞的mtDNA拷贝数没有增加。然后我们通过转染shRNA-TFAM质粒或用溴化乙锭处理来下调线粒体DNA拷贝数，发现肿瘤细胞对DDP或DOX的敏感性显着增加。此外，我们观察到活性氧（ROS）水平显着增加，在肿瘤细胞与较低的mtDNA拷贝数，这可能与抗氧化基因表达水平低。最后，我们用硫辛酸或N-乙酰-L-半胱氨酸挽救了肿瘤细胞中ROS的增加，发现凋亡率下降。我们的研究表明，mtDNA拷贝数的增加是肿瘤细胞防止凋亡的一种自我保护机制，而mtDNA拷贝数的减少增加了肿瘤细胞内的ROS水平，增加了肿瘤细胞对化疗药物的敏感性，增加了凋亡率。该研究为mtDNA拷贝数变异可能成为肿瘤临床治疗的新靶点提供了证据。
Many cancer drugs are toxic to cells by activating apoptotic pathways. Previous studies have shown that mitochondria have key roles in apoptosis in mammalian cells, but the role of mitochondrial DNA (mtDNA) copy number variation in the pathogenesis of tumor cell apoptosis remains largely unknown. We used the HEp-2, HNE2, and A549 tumor cell lines to explore the relationship between mtDNA copy number variation and cell apoptosis. We first induced apoptosis in three tumor cell lines and one normal adult human skin fibroblast cell line (HSF) with cisplatin (DDP) or doxorubicin (DOX) treatment and found that the mtDNA copy number significantly increased in apoptotic tumor cells, but not in HSF cells. We then downregulated the mtDNA copy number by transfection with shRNA-TFAM plasmids or treatment with ethidium bromide and found that the sensitivity of tumor cells to DDP or DOX was significantly increased. Furthermore, we observed that levels of reactive oxygen species (ROS) increased significantly in tumor cells with lower mtDNA copy numbers, and this might be related to a low level of antioxidant gene expression. Finally, we rescued the increase of ROS in tumor cells with lipoic acid or N-acetyl-L-cysteine and found that the apoptosis rate decreased. Our studies suggest that the increase of mtDNA copy number is a self-protective mechanism of tumor cells to prevent apoptosis and that reduced mtDNA copy number increases ROS levels in tumor cells, increases the tumor cells' sensitivity to chemotherapeutic drugs, and increases the rate of apoptosis. This research provides evidence that mtDNA copy number variation might be a promising new therapeutic target for the clinical treatment of tumors.