Early spatiotemporal-specific changes in intermediate signals are predictive of cytotoxic sensitivity to TNF? and co-treatments
Loo, L.-H Bougen-Zhukov, N.M Tan, W.-L.C
Bougen-Zhukov, N.M
Tan, W.-L.C
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Alternative Title
Abstract
Signaling pathways can generate different cellular responses to the same cytotoxic agents. Current quantitative models for predicting these differential responses are usually based on large numbers of intracellular gene products or signals at different levels of signaling cascades. Here, we report a study to predict cellular sensitivity to tumor necrosis factor alpha (TNF?) using high-throughput cellular imaging and machine-learning methods. We measured and compared 1170 protein phosphorylation events in a panel of human lung cancer cell lines based on different signals, subcellular regions, and time points within one hour of TNF? treatment. We found that two spatiotemporal-specific changes in an intermediate signaling protein, p90 ribosomal S6 kinase (RSK), are sufficient to predict the TNF? sensitivity of these cell lines. Our models could also predict the combined effects of TNF? and other kinase inhibitors, many of which are not known to target RSK directly. Therefore, early spatiotemporal-specific changes in intermediate signals are sufficient to represent the complex cellular responses to these perturbations. Our study provides a general framework for the development of rapid, signaling-based cytotoxicity screens that may be used to predict cellular sensitivity to a cytotoxic agent, or identify co-treatments that may sensitize or desensitize cells to the agent. © The Author(s) 2017.
Keywords
antineoplastic agent, protein kinase inhibitor, transcriptome, tumor marker, tumor necrosis factor, biological model, cell survival, dose response, drug effect, drug resistance, gene expression regulation, genetics, human, lung tumor, metabolism, mutation, non small cell lung cancer, phosphorylation, protein transport, signal transduction, tumor cell line, Antineoplastic Agents, Biomarkers, Tumor, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Survival, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms, Models, Biological, Mutation, Phosphorylation, Protein Kinase Inhibitors, Protein Transport, Signal Transduction, Transcriptome, Tumor Necrosis Factor-alpha
Source Title
Scientific Reports
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Series/Report No.
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Rights
Attribution 4.0 International
Date
2017
DOI
10.1038/srep43541
Type
Article