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Genetically Targeted Cancer Therapy

Tumor Destruction by PKR Activation

  • Targeted Therapeutics
  • Published:
American Journal of Pharmacogenomics

Abstract

The is a double-stranded RNA-activated protein kinase (PKR) has been largely investigated for its key role in viral host defense. Although best characterized by its function in mediating the antiviral and antiproliferative effects of interferon (IFN), PKR is also implicated in transcriptional regulation, cell differentiation, signal transduction, and tumor suppression. However, recent findings identifying PKR as an important effector of apoptosis have led to an increased interest in PKR modulation as an antitumor strategy. PKR can either be up-regulated through direct induction by the transcription factor E2F-1, or it can be activated through direct protein-protein interactions with the melanoma differentiation-associated gene-7 (MDA7, IL-24). Additionally, the intracellular formation of double-stranded RNA by transfection with antisense RNA complementary to tumor-specific RNA sequences can induce PKR activation and apoptosis selective to these tumor cells.

The growing application of viral vector-based gene therapies and oncolytic, replicating viruses that must elude viral defense in order to be effective, has also drawn attention to PKR. Oncolytic viruses, like the attenuated herpes simplex virus R3616, the vesicular stomatitis virus, or reovirus, specifically replicate in tumor cells only because the viral host defense in the permissive cells is suppressed.

In this article we review the role of PKR as an effector of apoptosis and a target for tumor treatment strategies and discuss the potential of PKR-modifying agents to treat patients with cancer. Targeted gene therapy against cancer can be approached by activation of PKR with the down-regulation of protein synthesis and induction of apoptosis, or by suppression of PKR with the propagation of oncolytic virus. Since the PKR pathway can be modified by many routes, antitumor therapies combining oncolytic virus, gene therapies, and chemotherapy with PKR modifiers are likely to emerge in the near future as therapeutic options in the treatment of patients with cancer.

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Acknowledgments

This investigation was supported in part by grants from The University of Texas M. D. Anderson Cancer Center Support Core (CA 16672), from the National Institutes of Health, Department of Health & Human Services, the Department of Defense (grant DAMD17-97-1-7162 to Dr Hunt), the Swiss Cancer League (grant BIL SKL 1129-02-2001), the Swiss Foundation for Cancer Treatment (grant 148 for Dr Vorburger), the Shooting Down Cancer Fund from the M. D. Anderson Cancer Center (for Dr Hunt), and the Cheryl Burguieres Book Signing Account from the M. D. Anderson Cancer Center (for Dr Hunt). ## The authors have no conflicts of interest directly relevant to the content of this review.

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  1. Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA

    Stephan A. Vorburger &  Kelly K. Hunt

  2. Department of Thoracic & Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA

    Abujiang Pataer & Stephen G. Swisher

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  1. Stephan A. Vorburger
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  2. Abujiang Pataer
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  3. Stephen G. Swisher
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  4. Kelly K. Hunt
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Correspondence to Kelly K. Hunt.

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Vorburger, S.A., Pataer, A., Swisher, S.G. et al. Genetically Targeted Cancer Therapy. Am J Pharmacogenomics 4, 189–198 (2004). https://doi.org/10.2165/00129785-200404030-00006

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