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Cytotoxic drug-induced, p53-mediated upregulation of caspase-8 in tumor cells

Oncogene volume 27, pages 783–793 (2008)Cite this article

Abstract

Apoptosis resistance is crucially involved in cancer development and progression, represents the leading cause for failure of anticancer therapy and is caused, for example, by downregulation of proapoptotic intracellular signaling molecules such as caspase-8. We found that the cytotoxic drugs methotrexate (MTX) and 5-fluorouracil (5-FU) were both able to sensitize resistant tumor cells for induction of apoptosis by p53-mediated upregulation of caspase-8. Increase in caspase-8 messenger RNA and protein expression disabled tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced proliferation and restored sensitivity toward TRAIL-induced apoptosis which was inhibited by transfection of p53 decoy oligonucleotides, p53 shRNA and caspase-8 shRNA. Upregulation of caspase-8 and sensitization toward TRAIL-induced apoptosis was found both in a broad panel of tumor cell lines with downregulated caspase-8 and in TRAIL-resistant primary tumor cells of children with acute leukemia. Taken together, we have identified caspase-8 as an important p53 target gene regulated by cytotoxic drugs. These findings highlight a new drug-induced modulation of physiological apoptosis pathways, which may be involved in successful anticancer therapy using MTX and 5-FU in leukemia and solid tumors over decades.

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Acknowledgements

We appreciate the skilled technical work of P Berger and D Föttinger. This work was supported by Wilhelm Sander-Stiftung, Deutsche Jose Carreras Leukämie Stiftung, FöFoLe no. 19-2005, Dr Helmut Legerlotz Stiftung and Bettina Bräu Stiftung (all to IJ), and the Deutsche Forschungsgemeinschaft (to SF).

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Authors and Affiliations

  1. Department of Oncology/Hematology, Dr von Haunersches Kinderspital, München, Germany

    H Ehrhardt, S Wittmann, M Maurer, A Borkhardt & I Jeremias

  2. Klinik für Kinder-und Jugendmedizin, Ulm, Germany

    S Häcker, K-M Debatin & S Fulda

  3. GSF – Research Center for Environment and Health, Munich, Germany

    A Toloczko & I Jeremias

  4. Division of Neonatology, Department of Obstetrics and Gynecology, University of Munich, Munich, Germany

    H Ehrhardt

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  1. H Ehrhardt
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  2. S Häcker
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  4. M Maurer
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  7. K-M Debatin
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  8. S Fulda
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  9. I Jeremias
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Correspondence to I Jeremias.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Ehrhardt, H., Häcker, S., Wittmann, S. et al. Cytotoxic drug-induced, p53-mediated upregulation of caspase-8 in tumor cells. Oncogene 27, 783–793 (2008). https://doi.org/10.1038/sj.onc.1210666

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