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Sensitization by Radio-Chemotherapy in Targeting Therapy for Survival Signal Transduction Pathways against Head and Neck Cancers

头颈癌生存信号转导通路靶向治疗中放化疗增敏

基本信息

批准号：
18591880
负责人：
YANE Katsunari
金额：
$ 2.36万
依托单位：
Nara Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591880/
关键词：
head and neck cancer molecular target siRNA radiotherapy chemotherapy p53 gene DNA repair apoptosis

项目摘要

NBS1 is essential for the repair of DNA double-strand breaks (DSBs) and may play a important role in the homologous recombination repair and nonhomologous end joining repair. In this study, we examined whether suppressed NBS1 expression by small interference RNA (siRNA) could enhance radiation sensitivity in cancer cells with different TP53 status. We used human tongue cancer cells differing in TP53 gene status (SAS/neo bearing wild-type TP53 or SAS/mp53 bearing mutant TP53). A DNA cassette expressing siRNA targeted for the NBS1 gene was transfected into those cell lines. Cellular levels of NBS1 and other proteins were analyzed using Western blotting. We found that the radiation sensitivity of SAS/neo and SAS/mp53 was enhanced by transfection of the DNA cassette. In the NBS1-siRNA-transfected cells, we observed decreased constitutive expression of NBS1 protein and decreased radiation-induced accumulation of phosphorylated NBS1 protein. In addition, radiation-induced expression of the transcription factor NF-kB was suppressed by NBS1-siRNA. Enhanced X-ray sensitivity after NBS1-siRNA transfection was achieved in TP53 wild-type cells and sensitivity was even more pronounced in TP53 mutant cells. Our data suggest that the sensitization to radiation results from NBS1-siRNA-mediated suppression of DNA repair and/ or X-ray-induced cell survival signaling pathways through NF-kB. siRNA targeting appears to be a novel radiation-sensitizing agent, particularly in human TP53 mutant cancer cells.

NBS 1是DNA双链断裂修复所必需的，在同源重组修复和非同源末端连接修复中可能发挥重要作用。在这项研究中，我们研究了通过小干扰RNA（siRNA）抑制NBS 1表达是否可以增强具有不同TP 53状态的癌细胞的辐射敏感性。我们使用TP 53基因状态不同的人舌癌细胞（携带野生型TP 53的SAS/neo或携带突变型TP 53的SAS/mp53）。将表达靶向NBS 1基因的siRNA的DNA盒转染到这些细胞系中。使用蛋白质印迹法分析NBS 1和其他蛋白质的细胞水平。我们发现，SAS/neo和SAS/mp53的辐射敏感性通过转染DNA盒而增强。在NBS 1-siRNA转染的细胞中，我们观察到NBS 1蛋白的组成性表达减少，并且辐射诱导的磷酸化NBS 1蛋白的积累减少。此外，辐射诱导的转录因子NF-κ B的表达被NBS 1-siRNA抑制。NBS 1-siRNA转染后，在TP 53野生型细胞中实现了增强的X射线敏感性，并且在TP 53突变细胞中的敏感性甚至更明显。我们的数据表明，对辐射的敏感性是由NBS 1-siRNA介导的DNA修复和/或X射线诱导的细胞存活信号通路通过NF-κ B的抑制引起的。siRNA靶向似乎是一种新的辐射增敏剂，特别是在人TP 53突变癌细胞中。