Integrating global gene expression and radiation survival parameters across the 60 cell lines of the National Cancer Institute Anticancer Drug Screen
Integrating global gene expression and radiation survival parameters across the 60 cell lines of the National Cancer Institute Anticancer Drug Screen
复制标题
DOI：
10.1158/0008-5472.can-07-2120
复制
发表时间：
2008-01-15
期刊：
影响因子：
11.2
通讯作者：
Fornace, Albert J., Jr.
中科院分区：
文献类型：
--
作者：
Amundson, Sally A.;Do, Khanh T.;Fornace, Albert J., Jr.
国家癌症研究所抗癌药物筛选（NCI-60）的60个细胞系构成了最广泛表征的体外癌细胞模型。他们已经测试了对超过100，000种潜在化疗药物的敏感性，并在DNA，RNA，蛋白质，功能和药理学水平上进行了广泛的分析。我们已经使用NCI-60细胞系和另外三个细胞系来开发癌细胞对电离辐射的反应的数据库。我们通过微阵列比较了克隆存活率、细胞凋亡和基因表达反应。虽然有几项研究已经分析了NCI-60中的相对基础基因表达，但这是第一次比较基因毒性应激反应中的大规模基因表达变化。22个基因在2-戈伊γ射线后存活率低的细胞中差异调节; 14个基因鉴定出对8戈伊更敏感的细胞系。与报道的基础基因表达模式不同，辐射引起的表达变化显示出很少的组织来源效应，除了从其他细胞类型中区分淋巴母细胞样细胞系。基础表达模式，但是，区分辐射敏感性和更耐线，可能是更多的信息比辐射响应签名。辐射数据中最引人注目的模式是在p53野生型系中优先上调的一组基因和在整个NCI-60组中下调的一组细胞周期调控基因。这些基因对伽马射线的反应似乎不受这些不同细胞群中无数遗传差异的影响;它代表了迄今为止观察到的对电离辐射最具渗透性的基因表达反应。
The 60 cell lines of the National Cancer Institute Anticancer Drug Screen (NCI-60) constitute the most extensively characterized in vitro cancer cell model. They have been tested for sensitivity to more than 100,000 potential chemotherapy agents and have been profiled extensively at the DNA, RNA, protein, functional, and pharmacologic levels. We have used the NCI-60 cell lines and three additional lines to develop a database of responses of cancer cells to ionizing radiation. We compared clonogenic survival, apoptosis, and gene expression response by microarray. Although several studies have profiled relative basal gene expression in the NCI-60, this is the first comparison of large-scale gene expression changes in response to genotoxic stress. Twenty-two genes were differentially regulated in cells with low survival after 2-Gy gamma-rays; 14 genes identified lines more sensitive to 8 Gy. Unlike reported basal gene expression patterns, changes in expression in response to radiation showed little tissue-of-origin effect, except for differentiating the lymphoblastoid cell lines from other cell types. Basal expression patterns, however, discriminated well between radiosensitive and more resistant lines, possibly being more informative than radiation response signatures. The most striking patterns in the radiation data were a set of genes up-regulated preferential in the p53 wild-type lines and a set of cell cycle regulatory genes down-regulated across the entire NCI-60 panel. The response of those genes to gamma-rays seems to be unaffected by the myriad of genetic differences across this diverse cell set; it represents the most penetrant gene expression response to ionizing radiation yet observed.