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Insertion of a nuclear factor kappa B DNA nuclear-targeting sequence potentiates suicide gene therapy efficacy in lung cancer cell lines

Cancer Gene Therapy volume 19, pages 675–683 (2012)Cite this article

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Abstract

Lung cancer currently causes the majority of cancer-related deaths worldwide and new treatments are in high demand. Gene therapy could be a promising treatment but currently lacks sufficient efficiency for clinical use, primarily due to limited cellular and nuclear DNA delivery. In the present study, we investigated whether it was possible to exploit the endogenous nuclear-shuttling activity by the nuclear factor kappa B (NFκB) system, which is highly prominent in many cancers as well as lung cancer. We observed that insertion of a DNA nuclear-targeting sequence (DTS) recognized by NFκB could improve plasmid nuclear delivery and enhance the therapeutic effect of a validated transcriptionally cancer-targeted suicide gene therapy system. A clear correlation between the number of inserted NFκB-binding sites and the therapeutic effect of the suicide system was observed in both small cell lung cancer (SCLC) and non-SCLC cell lines. The effect was observed to be due to elevated nuclear translocation of the suicide gene-encoding plasmids. The results show that a significant improvement of gene therapeutic efficiency can be obtained by increasing the intracellular trafficking of therapeutic DNA. This is to our knowledge the first time a DTS strategy has been implemented for suicide gene therapy.

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Acknowledgements

We thank Pia Pedersen (Department of Radiation Biology) and Lynn Gottfried (Department of Pediatrics) for technical assistance. This work was funded by grants from the University of Copenhagen, the Danish Cancer Society, the Novo Nordisk Foundation, the Aase and Ejnar Danielsens Foundation, the Katrine and Vigo Skovgaards Foundation and the Beckett Foundation.

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Authors and Affiliations

  1. Department of Radiation Biology, Copenhagen University Hospital, Copenhagen, Denmark

    F Cramer, C L Christensen, T T Poulsen & H S Poulsen

  2. Department of Pediatrics, University of Rochester, Rochester, NY, USA

    M A Badding & D A Dean

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  1. F Cramer
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  2. C L Christensen
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  3. T T Poulsen
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  4. M A Badding
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  5. D A Dean
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Correspondence to H S Poulsen.

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Cramer, F., Christensen, C., Poulsen, T. et al. Insertion of a nuclear factor kappa B DNA nuclear-targeting sequence potentiates suicide gene therapy efficacy in lung cancer cell lines. Cancer Gene Ther 19, 675–683 (2012). https://doi.org/10.1038/cgt.2012.54

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