Abstract
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 preferentially 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.
Highlights
In the 1980s, the National Cancer Institute (NCI) selected 60 cell lines representing nine tumor types and established the NCI-60 panel of cancer cell lines as a toolNote: Supplementary data for this article are available at Cancer Research Online.I2008 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-07-2120 for in vitro drug screening
Clonogenic survival after exposure to 0, 2, 5, or 8 Gy of g-rays was measured for the NCI-60 and three additional cell lines
The NCI-60: Ionizing Radiation and Gene Expression lines, dose points at 1 and 6 Gy were added to clarify the shape of the survival curve
Summary
Data from the NCI-60 screen have led to identification of mechanisms of drug action, approval of new chemotherapy drugs (e.g., bortezomib), and basic advances in the understanding of cancer mechanisms [1,2,3]. Continued screening of potential chemotherapy agents and molecular characterization of the cell lines make this information-rich system a valuable resource [4]. We began early gene expression studies in the NCI-60 with the measurement of g-ray induction of three genes [5]. The study identified a subset of p53 wild-type cell lines with defective GADD45A induction by g-rays. In a subsequent study [7], we analyzed basal expression levels of 10 genes in the NCI-60 cell lines, finding a striking overall correlation between sensitivity to 122 chemotherapy agents and expression levels of BCL2L1 (BCL-XL). The correlation was independent of growth rate and TP53 status
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