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Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy
08:51

Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy

Published on: April 3, 2018

JNK-deficiency enhanced oncolytic vaccinia virus replication and blocked activation of double-stranded RNA-dependent

W Hu1, W Hofstetter, W Guo

  • 1Department of Thoracic and Cardiovascular Surgery, The University of Texas MD, Anderson Cancer Center, Houston, TX 77030, USA.

Cancer Gene Therapy
|June 7, 2008
PubMed

Insights

The c-Jun NH2-terminal kinase (JNK) pathway significantly impacts vaccinia virus replication and cancer cell killing. JNK deficiency enhances viral replication and susceptibility to oncolytic vaccinia virus, suggesting JNK

Area of Science:

  • Virology
  • Cancer Biology
  • Immunology

Background:

  • Vaccinia virus is a promising oncolytic agent for cancer therapy.
  • Host factors influencing vaccinia virus replication and oncolysis are not fully understood.
  • Interferon-induced protein kinase (PKR) and RNase L are known to inhibit viral replication.

Purpose of the Study:

  • To investigate the role of c-Jun NH2-terminal kinase (JNK) in vaccinia virus replication.
  • To determine JNK's involvement in vaccinia virus-mediated host cell killing.
  • To elucidate the mechanism by which JNK affects vaccinia virus oncolysis.

Main Methods:

  • Utilized JNK knockout mouse embryonic fibroblasts (MEFs) and wild-type MEFs.
  • Employed JNK inhibitors and dominant-negative JNK constructs in human cancer cells.
  • Assessed viral replication, infectious progeny production, and cell killing.
  • Investigated the impact on PKR activation and expression.

Main Results:

  • JNK-deficient MEFs showed significantly increased vaccinia virus replication and susceptibility.
  • Viral replication and progeny production were up to 100-fold higher in JNK-deficient cells.
  • JNK deficiency blocked or diminished oncolytic virus infection-mediated PKR activation.
  • Ectopic PKR expression in JNK-deficient MEFs restored vaccinia virus replication to wild-type levels.

Conclusions:

  • JNK signaling is crucial for efficient vaccinia virus replication and oncolysis.
  • JNK is required for vaccinia virus to effectively activate PKR.
  • Modulating JNK activity could enhance the efficacy of vaccinia virus-based cancer therapy.

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