Suppression of IFN-induced transcription underlies IFN defects generated by activated Ras/MEK in human cancer cells

• Published in: PloS one Vol. 7; no. 9; p. e44267
• Main Authors: Christian, Sherri L, Zu, Dong, Licursi, Maria, Komatsu, Yumiko, Pongnopparat, Theerawat, Codner, Dianne A, Hirasawa, Kensuke
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07.09.2012; Public Library of Science (PLoS)
• Subjects: alpha -Interferon; Analysis; Antiviral agents; Antiviral Agents - pharmacology; Apoptosis; Bioinformatics; Biological activity; Biological response modifiers; Biology; Butadienes; Cancer; Cancer cells; Cell differentiation; Cell Line, Tumor; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; Deoxyribonucleic acid; Differentiation; Differentiation (biology); DNA; DNA microarrays; Drug Resistance, Neoplasm - drug effects; Enzyme Activation - drug effects; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Genes; Genetic research; Humans; Infections; Interferon; Interferons - pharmacology; Kinases; Leukemia; Matrilysin; Medicine; MEK inhibitors; Metabolism; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - metabolism; Molecular Sequence Annotation; Mutation; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - pathology; Nitriles; Oligonucleotide Array Sequence Analysis; Oncolysis; Oncolytic viral therapy; Physiological aspects; Proteins; Ras protein; ras Proteins - metabolism; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; Science; Sensitivity; Signal transduction; Signaling; Stat2 protein; Transcription; Transcription (Genetics); Transcription, Genetic - drug effects; Tumor cell lines; Viruses; α-Interferon; Canada
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0044267

Certain oncolytic viruses exploit activated Ras signaling in order to replicate in cancer cells. Constitutive activation of the Ras/MEK pathway is known to suppress the effectiveness of the interferon (IFN) antiviral response, which may contribute to Ras-dependent viral oncolysis. Here, we identified 10 human cancer cell lines (out of 16) with increased sensitivity to the anti-viral effects of IFN-α after treatment with the MEK inhibitor U0126, suggesting that the Ras/MEK pathway underlies their reduced sensitivity to IFN. To determine how Ras/MEK suppresses the IFN response in these cells, we used DNA microarrays to compare IFN-induced transcription in IFN-sensitive SKOV3 cells, moderately resistant HT1080 cells, and HT1080 cells treated with U0126. We found that 267 genes were induced by IFN in SKOV3 cells, while only 98 genes were induced in HT1080 cells at the same time point. Furthermore, the expression of a distinct subset of IFN inducible genes, that included RIGI, GBP2, IFIT2, BTN3A3, MAP2, MMP7 and STAT2, was restored or increased in HT1080 cells when the cells were co-treated with U0126 and IFN. Bioinformatic analysis of the biological processes represented by these genes revealed increased representation of genes involved in the anti-viral response, regulation of apoptosis, cell differentiation and metabolism. Furthermore, introduction of constitutively active Ras into IFN sensitive SKOV3 cells reduced their IFN sensitivity and ability to activate IFN-induced transcription. This work demonstrates for the first time that activated Ras/MEK in human cancer cells induces downregulation of a specific subset of IFN-inducible genes.