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VSV virotherapy improves chemotherapy by triggering apoptosis due to proteasomal degradation of Mcl-1

Gene Therapy volume 16, pages 849–861 (2009)Cite this article

Abstract

Overexpression of myeloid cell leukemia 1 protein (Mcl-1), an anti-apoptotic B-cell lymphoma 2 (Bcl-2) family member, contributes to chemotherapy resistance of tumors. The short half-life of Mcl-1 makes it an interesting target for therapeutic agents that negatively interfere with cellular protein biosynthesis, such as oncolytic viruses. Vesicular Stomatitis Virus (VSV) has been established as the oncolytic virus that efficiently disrupts de novo protein biosynthesis of infected cells. Here, we show that after VSV infection, Mcl-1 protein levels rapidly declined, whereas the expression of other members of the Bcl-2 family remained unchanged. Mcl-1 elimination was a consequence of proteasomal degradation, as overexpression of a degradation-resistant Mcl-1 mutant restored Mcl-1 levels. Mcl-1 rescue inhibited apoptosis and thereby confirmed that Mcl-1 downregulation contributes to VSV-induced apoptosis. In vitro, VSV virotherapy in combination with chemotherapy revealed an enhanced therapeutic effect compared with the single treatments, which could be reverted by Mcl-1 rescue or RNA interference (RNAi)-mediated knockdown of pro-apoptotic Bax and Bak proteins. Finally, in a tumor mouse model, combinations of doxorubicin and VSV showed a superior therapeutic efficacy compared with VSV or doxorubicin alone. In summary, our data indicate that VSV virotherapy is an attractive strategy to overcome tumor resistance against conventional chemotherapy by elimination of Mcl-1.

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Acknowledgements

We thank Meriame Nassiri and Gisela Weier for their excellent assistance in animal experiments, preparation of tissue sections and histological stainings. Financial support was provided by: EU-project, Netsensor' (Contract no. 12948), Deutsche Forschungsgemeinschaft (DFG) clinical research group KFO119/2, DFG KU 1213/3-2, Deutsche Krebshilfe 10-2078-Ku2. We thank the Foundation of the German Economy (Stiftung der Deutschen Wirtschaft) for financing the position of Peter Schache.

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  1. F Kühnel and S Kubicka: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany

    P Schache, E Gürlevik, N Strüver, N Woller, N Malek, L Zender, M Manns, F Kühnel & S Kubicka

  2. Department of Microbiology, University of Iowa, Iowa City, IA, USA

    T Wirth

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  1. P Schache
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Correspondence to F Kühnel or S Kubicka.

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Schache, P., Gürlevik, E., Strüver, N. et al. VSV virotherapy improves chemotherapy by triggering apoptosis due to proteasomal degradation of Mcl-1. Gene Ther 16, 849–861 (2009). https://doi.org/10.1038/gt.2009.39

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