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The sirtuin 1/2 inhibitor tenovin-1 induces a nonlinear apoptosis-inducing factor-dependent cell death in a p53 null Ewing’s sarcoma cell line

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Summary

The sirtuin 1/2 inhibitor tenovin-1 activates p53 and may have potential in the management of cancer. Here, we investigated the responsiveness of Ewing’s sarcoma cells to tenovin-1. We examined its effects in two Ewing’s sarcoma cell lines with different p53 status, i.e. in p53 wild-type and p53 null cells. Effects were assessed by flow cytometric analyses of cell death, mitochondrial membrane depolarization and reactive oxygen species (ROS) generation, by caspase 3/7 activity measurement, by mRNA expression profiling and by immunoblotting. Tenovin-1 elicited caspase-mediated cell death in p53 wild-type cells, but caspase-independent cell death in p53 null cells. Remarkably, it induced a nonlinear concentration response in the latter: low concentrations of tenovin-1 were much more effective than were higher concentrations. Tenovin-1’s effects in p53 null cells involved gene expression changes of Bcl-2 family members, mitochondrial membrane depolarization, nuclear translocation of apoptosis-inducing factor, ROS formation and DNA damage; all these effects followed a bell-shaped pattern. In conclusion, our results provide new insights into tenovin-1’s mode of action by demonstrating that it can induce different pathways of cell death.

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Funding

Christian Marx was supported by the Richard-Winter-Stiftung and the Deutsche Forschungsgemeinschaft (RTG 1715 SP13).

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Author notes

  1. Christian Marx and Lisa Marx-Blümel contributed equally to this work.

Authors and Affiliations

  1. Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany

    Christian Marx & Zhao-Qi Wang

  2. Department of Pediatric Hematology and Oncology, Children’s Clinic, Jena University Hospital, Jena, Germany

    Lisa Marx-Blümel, Nora Lindig, Sabine Becker, Susan Wittig, James F. Beck & Jürgen Sonnemann

  3. Research Center Lobeda, Jena University Hospital, Jena, Germany

    Lisa Marx-Blümel, Nora Lindig, Sabine Becker, Susan Wittig & Jürgen Sonnemann

  4. Department of Human Nutrition, Institute of Nutrition, Friedrich Schiller University Jena, Jena, Germany

    René Thierbach & Doerte Hoelzer

  5. Host Septomics, Jena University Hospital, Jena, Germany

    Roland Lehmann & Hortense Slevogt

  6. Department of Biochemistry, Center for Molecular Biomedicine, Institute for Biochemistry and Biophysics, Friedrich Schiller University Jena, Jena, Germany

    Thorsten Heinzel

  7. Klinik für Kinder- und Jugendmedizin, Friedrich-Schiller-Universität Jena, Am Klinikum 1, D-07747, Jena, Germany

    Jürgen Sonnemann

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  1. Christian Marx
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  2. Lisa Marx-Blümel
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Correspondence to Jürgen Sonnemann.

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Marx, C., Marx-Blümel, L., Lindig, N. et al. The sirtuin 1/2 inhibitor tenovin-1 induces a nonlinear apoptosis-inducing factor-dependent cell death in a p53 null Ewing’s sarcoma cell line. Invest New Drugs 36, 396–406 (2018). https://doi.org/10.1007/s10637-017-0541-1

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  • DOI: https://doi.org/10.1007/s10637-017-0541-1

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