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Rac1 is required for oncolytic NDV replication in human cancer cells and establishes a link between tumorigenesis and sensitivity to oncolytic virus

Oncogene volume 29, pages 2205–2216 (2010)Cite this article

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Abstract

Oncolytic Newcastle disease virus (NDV) replicates selectively in most human tumor cells but not in normal cells. The relationship between tumorigenesis and the selective susceptibility of most tumor cells to oncolytic NDV replication is poorly understood. A multistage skin carcinogenesis model derived from non-tumorigenic HaCaT cells was used to systematically investigate the molecular mechanisms involved in the oncolytic NDV-sensitivity associated with tumorigenic transformation. No significant differences in interferon signaling were observed between the virus-sensitive tumor cells and the virus-resistant non-tumorigenic parental cells. Oncogenic H-Ras, which had been used for tumorigenic transformation, was shown to be necessary for virus replication but was not sufficient to render cells susceptible to NDV replication. By using an siRNA screening approach to search for virus-sensitizing genes in the tumorigenic cells, we could identify the small GTPase Rac1 as an oncogenic protein that is essential for NDV replication and anchorage-independent growth in tumorigenic cells. Furthermore, Rac1 expression was sufficient to render non-tumorigenic cells susceptible to NDV replication and to oncolytic cytotoxicity. This study establishes Rac1 as a link between tumorigenesis and oncolytic virus sensitivity in the HaCaT multistage skin carcinogenesis model.

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Acknowledgements

The authors thank Katja Köckritz, Steve Baethge, Anica Hoegner and Andreas Jung for their excellent technical assistance and Sanna-Maria Käkönen and David Light for carefully reading this paper. This work was in part supported by a grant from the Tumorzentrum Heidelberg–Mannheim to Petra Boukamp.

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Authors and Affiliations

  1. Bayer Schering Pharma AG, Global Drug Discovery, Berlin, Germany

    J Puhlmann, F Puehler, D Mumberg & R Beier

  2. Institute for Biology, FU Berlin, Berlin, Germany

    J Puhlmann

  3. Division of Genetics of Skin Carcinogenesis, Deutsches Krebsforschungszentrum, Heidelberg, Germany

    P Boukamp

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  1. J Puhlmann
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  2. F Puehler
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Correspondence to R Beier.

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Competing interests

Jenny Puhlmann received a commercial research grant from Bayer Schering Pharma AG. Florian Puehler, Dominik Mumberg and Rudolf Beier are employees and shareholders of Bayer Schering Pharma AG.

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Puhlmann, J., Puehler, F., Mumberg, D. et al. Rac1 is required for oncolytic NDV replication in human cancer cells and establishes a link between tumorigenesis and sensitivity to oncolytic virus. Oncogene 29, 2205–2216 (2010). https://doi.org/10.1038/onc.2009.507

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