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Therapy

TNF-α-converting enzyme (TACE/ADAM17)-dependent loss of CD30 induced by proteasome inhibition through reactive oxygen species

Leukemia volume 24, pages 51–57 (2010)Cite this article

Abstract

Combinations with proteasome inhibitors are currently being investigated to improve the therapy of hematological malignancies. We previously found that proteasome inhibition by bortezomib failed to sensitize anti-CD30 antibody (Ab)-based lymphoma cell killing. In this study, we demonstrate in L540 Hodgkin's lymphoma cells that proteasome inhibition not only communicates apoptosis but also more rapidly causes a loss of CD30 antigen from cell membrane and a simultaneous release of soluble CD30, a targeting competitor. This shedding was catalyzed by the tumor necrosis factor (TNF)-α-converting enzyme (TACE, ADAM17) and blocked by the ADAM17-selective inhibitor, Ro32-7315. In parallel with CD30 shedding, bortezomib caused the generation of reactive oxygen species (ROS). As apoptosis and shedding were inhibited by the radical scavenger, N-acetyl-L-cysteine, ROS might have a pivotal function in both effects. In contrast, the pan-caspase inhibitor, zVAD-fmk, blocked bortezomib-induced apoptosis but not CD30 shedding, and Ro32-7315 blocked shedding but allowed apoptosis. This suggests independent terminal signaling pathways that are conflicting in Ab-based immunotherapy. Consequently, shedding inhibition substantially improved the synergistic antitumor efficacy of the human anti-CD30 Ab, MDX-060, and bortezomib. As proteasome inhibition also stimulated loss of TNF receptors, interleukin-6 receptor and syndecan-1 in different leukemia and lymphoma cell lines, we concluded that proteasome inhibition might impede targeted therapy against antigens susceptible to shedding.

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Acknowledgements

We thank Gisela Schön for excellent technical assistance. This study was supported by grants from Deutsche Krebshilfe to HPH and AE (106473) and from the DFG to EPvS (Str 530/5-1). AMV, KSR, VLS, KW, AC performed research and analyzed data EPvS, DAE, BB, VRS, H-WK, SR-J, AE and HPH designed the research and analyzed data, HPH wrote the paper.

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Authors and Affiliations

  1. Department I of Internal Medicine, Laboratory of Immunotherapy, University Clinic Cologne, Cologne, Germany

    A M Vahdat, K S Reiners, V L Simhadri, D A Eichenauer, B Böll, V R Simhadri, A Engert, E P von Strandmann & H P Hansen

  2. Department of Biochemistry, University of Kiel, Kiel, Germany

    A Chalaris & S Rose-John

  3. Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany

    K Wiegmann

  4. Roche Diagnostics Pharma Research, Penzberg, Germany

    H-W Krell

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  1. A M Vahdat
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Correspondence to H P Hansen.

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Vahdat, A., Reiners, K., Simhadri, V. et al. TNF-α-converting enzyme (TACE/ADAM17)-dependent loss of CD30 induced by proteasome inhibition through reactive oxygen species. Leukemia 24, 51–57 (2010). https://doi.org/10.1038/leu.2009.230

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