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Apoptin-induced cell death is modulated by Bcl-2 family members and is Apaf-1 dependent

Oncogene volume 25, pages 2213–2222 (2006)Cite this article

Abstract

Apoptin, a chicken anemia virus-derived protein, selectively induces apoptosis in transformed but not in normal cells, thus making it a promising candidate as a novel anticancer therapeutic. The mechanism of apoptin-induced apoptosis is largely unknown. Here, we report that contrary to previous assumptions, Bcl-2 and Bcl-xL inhibit apoptin-induced cell death in several tumor cell lines. In contrast, deficiency of Bax conferred resistance, whereas Bax expression sensitized cells to apoptin-induced death. Cell death induction by apoptin was associated with cytochrome c release from mitochondria as well as with caspase-3 and -7 activation. Benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, a broad spectrum caspase inhibitor, was highly protective against apoptin-induced cell death. Apoptosis induced by apoptin required Apaf-1, as immortalized Apaf-1-deficient fibroblasts as well as tumor cells devoid of Apaf-1 were strongly protected. Thus, our data indicate that apoptin-induced apoptosis is not only Bcl-2- and caspase dependent, but also engages an Apaf-1 apoptosome-mediated mitochondrial death pathway.

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Abbreviations

AMC:

7-aminomethyl-4-coumarin

CAV:

chicken anemia virus

GFP:

green fluorescent protein

HUVEC:

human umbilical vein endothelial cell

zVAD-fmk:

benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone

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Acknowledgements

This work was in part supported by grants from the ‘Deutsche Krebshilfe' and the DFG. ML is supported by CIHR ‘Canada Research Chair’ and MHRC programs. SM acknowledges the generous support from CCMF. We are grateful to Drs J Prehn, RU Jänicke, F Prinz, F Cecconi, M Jäättela, LC Murphy for providing cell lines, expertise and reagents. We are in debt also to A Kemp and A Kania for help with experiments.

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Author notes

  1. M Burek and S Maddika: These authors contributed equally to this study.

  2. K Schulze-Osthoff and M Los: These authors share equal senior authorship.

Authors and Affiliations

  1. Department of Immunology and Cell Biology, University of Münster, Münster, Germany

    M Burek & C J Burek

  2. Manitoba Institute of Cell Biology, CancerCare Manitoba, Canada

    S Maddika & M Los

  3. Department of Hematology, Oncology and Tumor Immunology, Charité, Berlin, Germany

    P T Daniel

  4. Institute of Molecular Medicine, University of Düsseldorf, Düsseldorf, Germany

    K Schulze-Osthoff

  5. Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada

    M Los

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  1. M Burek
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Correspondence to K Schulze-Osthoff.

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Burek, M., Maddika, S., Burek, C. et al. Apoptin-induced cell death is modulated by Bcl-2 family members and is Apaf-1 dependent. Oncogene 25, 2213–2222 (2006). https://doi.org/10.1038/sj.onc.1209258

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