The RAS/Raf1/MEK/ERK signaling pathway facilitates VSV-mediated oncolysis: Implication for the defective interferon response in cancer cells

Josh A. Noser, Amber A. Mael, Ryuta Sakuma, Seiga Ohmine, Paola Marcato, Patrick W K Lee, Yasuhiro H Ikeda

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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 IFNα treatment no longer protected the RAS- or Raf1-overexpressing cells from VSV infection, responsiveness to IFNα was restored following treatment with the mitogen-activated protein kinase kinase (MEK) inhibitor U0126. Similarly, human cancer-derived cell lines became more responsive to IFNα in conjunction with U0126 treatment. Intriguingly, dual treatment with both IFNα and U0126 severely reduced the levels of viral RNAs in the infected cells. Moreover, cancer cells showed defects in inducing an IFNα-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 IFNα-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.

Original languageEnglish (US)
Pages (from-to)1531-1536
Number of pages6
JournalMolecular Therapy
Volume15
Issue number8
DOIs
StatePublished - Aug 2007

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Vesicular Stomatitis
MAP Kinase Signaling System
Interferons
Viruses
Neoplasms
Mitogen-Activated Protein Kinase Kinases
Oncolytic Viruses
RNA Viruses
Extracellular Signal-Regulated MAP Kinases
Viral RNA
Virus Diseases
Protein Kinases
Up-Regulation
Cell Line
U 0126

ASJC Scopus subject areas

  • Molecular Biology

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The RAS/Raf1/MEK/ERK signaling pathway facilitates VSV-mediated oncolysis : Implication for the defective interferon response in cancer cells. / Noser, Josh A.; Mael, Amber A.; Sakuma, Ryuta; Ohmine, Seiga; Marcato, Paola; Lee, Patrick W K; Ikeda, Yasuhiro H.

In: Molecular Therapy, Vol. 15, No. 8, 08.2007, p. 1531-1536.

Research output: Contribution to journalArticle

Noser, Josh A. ; Mael, Amber A. ; Sakuma, Ryuta ; Ohmine, Seiga ; Marcato, Paola ; Lee, Patrick W K ; Ikeda, Yasuhiro H. / The RAS/Raf1/MEK/ERK signaling pathway facilitates VSV-mediated oncolysis : Implication for the defective interferon response in cancer cells. In: Molecular Therapy. 2007 ; Vol. 15, No. 8. pp. 1531-1536.
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