Mitochondrial DNA determines the cellular response to cancer therapeutic agents
Mitochondrial DNA determines the cellular response to cancer therapeutic agents
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DOI：
10.1038/sj.onc.1203056
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发表时间：
1999-11-18
期刊：
影响因子：
8
通讯作者：
Keshav, KF
中科院分区：
文献类型：
--
作者：
Singh, KK;Russell, J;Keshav, KF
线粒体基因组突变导致线粒体功能障碍的报道在多种癌症中都有报道。然而，这些发现在细胞对癌症治疗药物的反应中的潜在意义尚不清楚。为了研究线粒体DNA(MitDNA)编码功能在肿瘤治疗反应中的重要性，我们测定了HSL2(Rho(+)，HeLa亚系)及其缺失mitDNA的衍生细胞系(Rho(O))在不同抗癌药物作用下的克隆存活率。我们发现，缺乏mitDNA的同基因Rho(O)细胞对阿霉素和光动力疗法(PDT)诱导的细胞死亡具有极强的抵抗力，而Rho(+)细胞株对阿霉素和光动力疗法(PDT)诱导的细胞死亡非常敏感。然而，这些细胞系对烷化剂或伽马辐射的反应没有可测量的差异。我们的研究表明，对阿霉素产生耐药性并不是由于细胞凋亡、细胞周期反应的改变，也不是由于同基因Rho(O)细胞摄取阿霉素。我们还证明了HeLa细胞暴露于阿霉素会导致mitDNA突变。这些研究提供了直接证据，证明mitDNA在细胞对癌症治疗药物的敏感性中发挥着重要作用。
Mutations in the mitochondrial genome leading to mitochondrial dysfunction have been reported in a variety of cancers. However, the potential implication of these findings in the cellular response to cancer therapeutic agents is unclear. To examine the importance of mitochondrial DNA (mitDNA) encoded functions in cancer therapeutic response, we determined the clonogenic survival of HSL2 (Rho(+), HeLa subline), and its derivative cell line lacking mitDNA (Rho(o)) after exposure to different anticancer agents. We found that isogenic Rho(o) cells lacking mitDNA were extremely resistant to adriamycin and photodynamic therapy (PDT) induced cell death, whereas the Rho(+) cell line was sensitive. However, there was no measurable difference in the responses of these cell lines to either alkylating agent or gamma-radiation. We show that the development of resistance to adriamycin was not due to changes in apoptotic cell death, cell cycle response or to the uptake of adriamycin in isogenic Rho(o) cells. We also demonstrate that exposure of HeLa cells to adriamycin leads to mutations in mitDNA. These studies provide direct evidence that mitDNA plays an important role in cellular sensitivity to cancer therapeutic agents.