Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Oncogenic Ras inhibits IRF1 to promote viral oncolysis

ABSTRACT: Oncolytic viruses exploit common molecular changes in cancer cells, which are not present in normal cells, to target and kill cancer cells. Ras transformation and defects in type I interferon (IFN)-mediated antiviral responses are known to be the major mechanisms underlying viral oncolysis. Previously, we demonstrated that oncogenic RAS/Mitogen-activated protein kinase kinase (Ras/MEK) activation suppresses the transcription of many IFN-inducible genes in human cancer cells, suggesting that Ras transformation underlies type I IFN defects in cancer cells. Here, we investigated how Ras/MEK downregulates IFN-induced transcription. By conducting promoter deletion analysis of IFN-inducible genes, namely guanylate-binding protein 2 and IFN gamma inducible protein 47 (Ifi47), we identified the IFN regulatory factor 1 (IRF1) binding site as the promoter region responsible for the regulation of transcription by MEK. MEK inhibition promoted transcription of the IFN-inducible genes in wild type mouse embryonic fibroblasts (MEFs), but not in IRF1?/? MEFs, showing that IRF1 is involved in MEK-mediated downregulation of IFN-inducible genes. Furthermore, IRF1 protein expression was lower in RasV12 cells compared with vector control NIH3T3 cells, but was restored to equivalent levels by inhibition of MEK. Similarly, the restoration of IRF1 expression by MEK inhibition was observed in human cancer cells. IRF1 re-expression in human cancer cells caused cells to become resistant to infection by the oncolytic vesicular stomatitis virus strain. Together, this work demonstrates that Ras/MEK activation in cancer cells downregulates transcription of IFN-inducible genes by targeting IRF1 expression, resulting in increased susceptibility to viral oncolysis. RNA was isolated from RasV12 transformed NIH/3T3 cells (RasV12 cells) treated with 20?M U0126 or 500U/ml IFN-?, or left untreated, for 6 hours, triplicate biological samples (9 samples).

ORGANISM(S): Mus musculus

SUBMITTER: Sherri Christian

PROVIDER: E-GEOD-49469 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Oncogenic Ras inhibits IRF1 to promote viral oncolysis.

Komatsu Y Y Christian S L SL Ho N N Pongnopparat T T Licursi M M Hirasawa K K

Oncogene 20141027 30

Oncolytic viruses exploit common molecular changes in cancer cells, which are not present in normal cells, to target and kill cancer cells. Ras transformation and defects in type I interferon (IFN)-mediated antiviral responses are known to be the major mechanisms underlying viral oncolysis. Previously, we demonstrated that oncogenic RAS/Mitogen-activated protein kinase kinase (Ras/MEK) activation suppresses the transcription of many IFN-inducible genes in human cancer cells, suggesting that Ras ...[more]

PMID: 25347735

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Project description:Radiation and chemotherapy represent standard-of-care cancer treatments, however most treated patients eventually experience tumor recurrence, treatment failure and metastatic dissemination with fatal consequences. To elucidate molecular mechanisms of resistance to radio- and chemo-therapy, we exposed human cancer cell lines (HeLa, MCF-7, and DU145) to clinically relevant doses of 5-azacytidine or ionizing radiation and compared the transcript profiles of all surviving cell subpopulations including non-adherent fraction. Stress-mobilized non-adherent cell fractions differed from other survivors in deregulation of hundreds of genes including those involved in interferon response. Exposure of cancer cells to interferon-gamma but not interferon-beta resulted in development of a heterogeneous non-adherent fraction comprising, besides apoptotic/necrotic cells, also live cells featuring active Notch signaling and expressing stem cell markers. Interferon-gamma-mediated loss of adhesion and anoikis-resistance required active Erk pathway interlinked with interferon signaling by IRF1, as chemical inhibition of MEK or siRNA-mediated knockdown of Erk1/2 and IRF1 prevented mobilization of the surviving non-adherent population. Noteworthy, among the top scoring genes upregulated in surviving non-adherent tumor cells induced by 5-azacytidine or irradiation was a skin-specific protein suprabasin (SBSN), a recently identified oncoprotein. SBSN expression required the activity of the MEK/Erk pathway, and siRNA-mediated knockdown of SBSN resulted in suppression of the non-adherent fraction in irradiated, interferon-gamma- and 5-azacytidine-treated cells, respectively. Consistently, ectopic expression of SBSN isoforms enhanced the non-adherent phenotype, suggesting functional participation of SBSN in genotoxic stress-induced phenotypic plasticity and stress resistance. The stress-induced expression of skin protein(s) in a subset of cancer cells indicates partial induction of a keratinocyte-like expression program. Overall, we propose that IFN and Erk signaling drive the heterogeneous response of cancer cells to genotoxic therapies and expression of keratinocyte-specific genes as key players in mobilization and survival of cancer stem-like cells, with implications for cancer evolution and therapy resistance.

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Oncogenic Ras inhibits IRF1 to promote viral oncolysis

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Oncogenic Ras inhibits IRF1 to promote viral oncolysis.

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