Cross-resistance to ionizing radiation in a murine leukemic cell line resistant to cis-dichlorodiammineplatinum(II):: Role of Ku autoantigen
Cross-resistance to ionizing radiation in a murine leukemic cell line resistant to cis-dichlorodiammineplatinum(II):: Role of Ku autoantigen
复制标题
对顺式二氯二氨铂(II)具有抗性的鼠白血病细胞系对电离辐射的交叉抗性：： Ku自身抗原的作用
DOI：
10.1124/mol.56.1.141
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发表时间：
1999-07-01
影响因子：
3.6
通讯作者：
Salles, B
中科院分区：
文献类型：
--
作者：
Frit, P;Canitrot, Y;Salles, B
顺-二氯二胺铂（CDDP；顺铂）通常与电离辐射（IR）联合用于治疗各种恶性肿瘤。在体外，许多观察结果表明，细胞系中获得CDDP抗性赋予了对IR的交叉抗性，但所涉及的分子机制尚未得到很好的证明。我们在此报告了小鼠抗cddp L1210细胞系（L1210/ 3r）的选择和特性，与亲本细胞（L1210/P）相比，由于修复双链断裂的能力增加，该细胞系表现出对IR的交叉抗性。在耐药细胞中，电泳迁移率转移试验显示dna末端结合活性增加，这可能归因于与抗体的延迟复合物的超移，自身抗原Ku。异二聚体Ku蛋白由86-kDa （Ku80）和70-kDa （Ku70）亚基组成，是DNA依赖蛋白激酶（DNA- pk）的DNA靶向成分，在哺乳动物DNA双链断裂修复中起关键作用。耐药细胞中ku结合活性的增加与Ku80亚基特异性的过表达有关。这些数据强烈表明，Ku活性的增加是对IR交叉抗性表型的原因。此外，这些观察结果，以及先前DNA-PK突变细胞的结果，提供了支持Ku/DNA-PK在抵抗政变中的作用的证据。这些结果表明，Ku活性可能是细胞对CDDP和IR反应之间的一个重要分子靶点。
cis-Dichlorodiammineplatinum(II) (CDDP; cisplatin) is commonly used in combination with ionizing radiation (IR) in the treatment of various malignancies. In vitro, many observations suggest that acquisition of CDDP resistance in cell lines confers cross-resistance to IR, but the molecular mechanisms involved have not been well documented yet. We report here the selection and characterization of a murine CDDP-resistant L1210 cell line (L1210/3R) that exhibits cross-resistance to IR because of an increased capacity to repair double-strand breaks compared with parental cells (L1210/P). In resistant cells, electrophoretic mobility shift assays revealed an increased DNA-end binding activity that could be ascribed, by supershifting the retardation complexes with antibodies, to the autoantigen Ku. The heterodimeric Ku protein, composed of 86-kDa (Ku80) and 70-kDa (Ku70) subunits, is the DNA-targeting component of DNA-dependent protein kinase (DNA-PK), which plays a critical role in mammalian DNA double-strand breaks repair. The increased Ku-binding activity in resistant cells was associated with an overexpression affecting specifically the Ku80 subunit. These data strongly suggest that the increase in Ku activity is responsible for the phenotype of cross-resistance to IR. In addition, these observations, along with previous results from DNA-PK- mutant cells, provide evidence in favor of a role of Ku/DNA-PK in resistance to COUP. These results suggest that Ku activity may be an important molecular target in cancer therapy at the crossroad between cellular responses to CDDP and IR.