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Oncogenic Ras inhibits IRF1 to promote viral oncolysis

Y Komatsu1, S L Christian2, N Ho1

  • 1Division of BioMedical Sciences, Faculty of Medicine, St John's, Newfoundland, Canada.

Oncogene
|October 28, 2014
PubMed

Insights

Oncogenic RAS/Mitogen-activated protein kinase kinase (Ras/MEK) activation in cancer cells suppresses interferon-inducible genes by targeting interferon regulatory factor 1 (IRF1). This IRF1 downregulation increases cancer cell susceptibility to oncolytic viruses.

Area of Science:

  • Virology
  • Molecular Biology
  • Cancer Research

Background:

  • Oncolytic viruses selectively target cancer cells by exploiting molecular alterations absent in normal cells.
  • Defects in type I interferon (IFN)-mediated antiviral responses, often linked to Ras transformation, are key to viral oncolysis.
  • Previous work indicated Ras/MEK activation suppresses IFN-inducible genes, suggesting a role in cancer's impaired antiviral defense.

Purpose of the Study:

  • To elucidate the mechanism by which Ras/MEK signaling downregulates IFN-induced gene transcription in cancer cells.
  • To investigate the role of interferon regulatory factor 1 (IRF1) in this Ras/MEK-mediated transcriptional suppression.
  • To determine the impact of IRF1 restoration on cancer cell susceptibility to oncolytic viruses.

Main Methods:

  • Promoter deletion analysis of IFN-inducible genes (guanylate-binding protein 2 and Ifi47) to identify regulatory regions.
  • MEK inhibition experiments in wild-type and IRF1-deficient mouse embryonic fibroblasts (MEFs).
  • Assessment of IRF1 protein expression in RasV12-transformed cells and human cancer cells, with and without MEK inhibition.
  • Evaluation of oncolytic vesicular stomatitis virus infection in human cancer cells with restored IRF1 expression.

Main Results:

  • The IRF1 binding site was identified as the critical promoter region regulated by MEK.
  • MEK inhibition restored IFN-inducible gene transcription in wild-type MEFs but not in IRF1(-/-) MEFs, confirming IRF1's role.
  • RasV12 transformation reduced IRF1 protein levels, which were restored by MEK inhibition in both mouse and human cancer cells.
  • Re-expression of IRF1 rendered human cancer cells resistant to oncolytic vesicular stomatitis virus infection.

Conclusions:

  • Ras/MEK activation in cancer cells downregulates IFN-inducible gene transcription by suppressing IRF1 expression.
  • This IRF1-mediated suppression enhances cancer cell susceptibility to oncolytic viral therapy.
  • Targeting the Ras/MEK/IRF1 pathway may represent a strategy to improve oncolytic virotherapy efficacy.

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