962. The Ras/Raf-1/MEK/ERK Signaling Pathway Dictates Host Cell Permissiveness to VSV Infection

Abstract

Vesicular stomatitis virus (VSV) can replicate with greater efficiency in malignant cells compared with normal cells. Although this selective replication appears caused by the defects in the interferon (IFN) system in malignant cells, the mechanisms which render the cells less responsive to interferon remain to be determined. Here we demonstrate that Ras/Raf-1/Erk pathway plays a major role in the defects in the IFN pathway. NIH/3T3 or human primary fibroblast cells stably expressing Ras or Raf-1 were no longer protected by IFN-alpha treatment from VSV infection. Upon treatment with the MEK inhibitor U0126 the response to INF was restored in these cells, suggesting the involvement of the Ras/Raf-1/MEK pathway. Importantly, most cancer cells examined showed elevated levels of phosphorylated Erk (p-Erk) and were less responsive to IFN-alpha treatment. Similar to the NIH/3T3 model, following treatment with U0126 the cells became far more protected by IFN-alpha treatment. Phosphorylated PKR and STAT1 were detectable in cancer cells following treatment with IFN-alpha regardless of treatment with U0126. The translation of viral proteins after treatment of IFN-alpha and U0126 was reduced to undetectable levels, suggesting that the elevated levels of p-Erk enhanced translation of viral proteins or the stability of viral mRNA under the presence of IFN-alpha. We will present our latest results on the relationship between p-Erk and the reduced INF response in cancer cells.