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Dual induction of PKR with E2F-1 and IFN-α to enhance gene therapy against hepatocellular carcinoma

Cancer Gene Therapy volume 15, pages 636–644 (2008)Cite this article

Abstract

Overexpression of the transcription factor E2F-1 induces apoptosis in tumor cells. This apoptotic effect is partly mediated through the induction of the double-stranded RNA-activated protein kinase (PKR). Here, we investigate if agents that upregulate PKR could enhance the apoptotic effect of E2F-1 overexpression in liver tumors. In human hepatocellular carcinoma (HCC) cells (Hep3B, HepG2, Huh7), adenovirus-mediated overexpression of E2F-1 (AdCMV-E2F) transcriptionally increased PKR mRNA. The subsequent increase of total and phosphorylated PKR protein was followed by induction of apoptosis. When AdCMV-E2F was combined with the PKR modifier interferon α (IFNα), PKR was additionally upregulated and both PKR activation and apoptosis were increased. Subcutaneous xenograft tumors were selectively targeted using an adenoviral vector expressing E2F-1 under the control of the human telomerase reverse transcriptase (hTERT) promoter (AdhTERT-E2F). Weekly systemic administration of AdhTERT-E2F inhibited tumor growth. The tumor suppressive effect of AdhTERT-E2F therapy was further enhanced in combination with IFNα.Our results demonstrate that PKR activating agents enhance the anti-tumor effect of E2F-1 overexpression in HCC in-vitro and in-vivo. Hence, modulation of PKR is a potential strategy to increase the efficacy of PKR-dependent anti-tumor therapies.

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Abbreviations

E2F-1:

E2F transcription factor 1

HCC:

hepatocellular carcinoma

IFNα:

interferon α

PKR:

double-stranded RNA-activated protein kinase

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Acknowledgements

We thank Dr Sunil Chada (Introgen Therapeutics Inc., Houston) for his support and for the AdCMV-Luc vector construct, as well as Dr Bingliang Fang for his help and for the AdCMV-E2F vector construct). This work was supported by Swiss National Science Foundation (SNF 3100A0-104023); Oncosuisse (OCS 01431-08-2003) (SAV).

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Authors and Affiliations

  1. Department of Visceral and Transplantation Surgery and Department of Clinical Research, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland

    V Roh, A Laemmle, D Stroka, D Candinas & S A Vorburger

  2. Department of Surgical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    U Von Holzen & K K Hunt

  3. Department of Clinical Pharmacology, Inselspital, University of Bern, Bern, Switzerland

    J-F Dufour

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  1. V Roh
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Correspondence to S A Vorburger.

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Roh, V., Laemmle, A., Von Holzen, U. et al. Dual induction of PKR with E2F-1 and IFN-α to enhance gene therapy against hepatocellular carcinoma. Cancer Gene Ther 15, 636–644 (2008). https://doi.org/10.1038/cgt.2008.34

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