title: The RAS/Raf1/MEK/ERK signaling pathway facilitates VSV-mediated oncolysis: implication for the defective interferon response in cancer cells.
abstract: Vesicular stomatitis virus (VSV) can replicate in malignant cells more efficiently than in normal cells. Although the selective replication appears to be caused by defects in the interferon (IFN) system in malignant cells, the mechanisms which render these cells less responsive to IFN remain poorly understood. Here we present evidence that an activated RAS/Raf1/MEK/ERK pathway plays a critical role in the defects. NIH 3T3 or human primary cells stably expressing active RAS or Raf1 were rapidly killed by VSV. Although IFNalpha treatment no longer protected the RAS- or Raf1-overexpressing cells from VSV infection, responsiveness to IFNalpha was restored following treatment with the mitogen-activated protein kinase kinase (MEK) inhibitor U0126. Similarly, human cancer-derived cell lines became more responsive to IFNalpha in conjunction with U0126 treatment. Intriguingly, dual treatment with both IFNalpha and U0126 severely reduced the levels of viral RNAs in the infected cells. Moreover, cancer cells showed defects in inducing an IFNalpha-responsive factor, MxA, which is known to block VSV RNA synthesis, and U0126 restored the MxA expression. Our observations suggest that activation of the extracellular signal-regulated protein kinase (ERK) signaling leads to the defect in IFNalpha-mediated upregulation of MxA protein, which facilitates VSV oncolysis. In view of the fact that 30% of all cancers have constitutive activation of the RAS/Raf1/MEK/ERK pathway, VSV would be an ideal oncolytic virus for targeting such cancers.
authors.affiliation: Molecular Medicine Program, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Josh A
authors.initials: JA
authors.lastname: Noser
authors.forename: Amber A
authors.initials: AA
authors.lastname: Mael
authors.forename: Ryuta
authors.initials: R
authors.lastname: Sakuma
authors.forename: Seiga
authors.initials: S
authors.lastname: Ohmine
authors.forename: Paola
authors.initials: P
authors.lastname: Marcato
authors.forename: Patrick Wk
authors.initials: PW
authors.lastname: Lee
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009570:Nitriles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D012328:RNA Viruses / Q000235:genetics; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D002070:Butadienes; D016898:Interferon-alpha; D009570:Nitriles; D047428:Protein Kinase Inhibitors; C113580:U 0126; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins