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Expression data from H1299 and H460 lung cancer cell lines

ABSTRACT: To identify a set of genes related to radioresistance, we analyzed the time-series gene expression profiles of radioresistant H1299 and radiosensitive H460 lung cancer cells in response to 2 Gy of ionizing radiation (IR) by performing quadratic regression (QR) analysis. Out of the 21,331 genes, we selected 6,538 genes by QR analysis from the gene expression profile of H460 cells and 6,086 genes from that of H1299 cells. Most of the genes identified in the H460 cells were classified into continuously up- or down-regulated groups, while the major QR groups were transiently changed groups in the H1299 cell line. From gene ontology analysis of the major QR groups, the DNA damage response was commonly enriched in both cell lines. DNA repair-related genes such as ATM, ATR, TP53BP1, BRCA1, MRE11, NBN and RAD50 were particularly up-regulated in H1299 cells. Suppression of these DNA repair-related genes using siRNA made H1299 cells radiosensitive to ionizing radiation. The data suggest that differential responses to DNA damage confer radioresistance to cancer cells, and provide potential novel targets for sensitizing radiotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE20549 | GEO | 2010/02/27

SECONDARY ACCESSION(S): PRJNA125307

REPOSITORIES: GEO

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Project description:Pancreatic ductal adenocarcinoma is one of the most aggressive cancer types and is well-known for its general low intrinsic radiosensitivity. In order to resolve mechanisms of how PDAC cells carry out radioresistance, a combination of proteomics and phosphoproteomics of two radiosensitive as well as radioresistant murine PDAC cell lines upon exposition to radiation was performed. A high depth of (phospho)proteomic identifications with > 13000 confidently identified phosphorylation sites and > 7800 proteins was achieved. Measuring the response of the phosphoproteome upon radiation revealed >700 phosphorylation sites on >400 proteins which were regulated in all four cell lines independently of the sensitivity status. This analysis validated already known radiomarkers but also uncovered novel members of the radiation-dependent signaling network in PDAC cells that were shown to be exclusively based on protein phosphorylation but not protein expression. Among those radioresponsive phosphoproteins were ten novel ATM substrates, which were validated by in vitro kinase assays. Comparison of radiosensitive and -resistant cells revealed a complex regulation of apoptotic processes, while changes in expression of DNA repair proteins seemed to not play a pivotal role. Especially increased expression of NQO1 was found to be a potential mechanism enabling resistance by clearing harmful reactive oxygen species from the PDAC cells. Further analysis of the radioresistance-associated-phosphoproteome, which was especially enriched in phosphoproteins with cytoskeleton organizational function, uncovered increased Actin dynamics and FAK activity in radioresistant cells. Both likely lead to increased survival, migrational capacity and perturbations in chromatin condensation which could oppose radiation. Based on the displayed adaptions in cellular protein expression and signaling in resistant PDAC cells, pharmacological inhibition of NQO1 and FAK could be suggested to sensitize towards radiation.

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Expression data from H1299 and H460 lung cancer cell lines

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