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Ceramide-induced killing of normal and malignant human lymphocytes is by a non-apoptotic mechanism

Oncogene volume 18, pages 2499–2506 (1999)Cite this article

Abstract

Synthetic ceramides induce apoptotic death of Jurkat and HL60 leukaemia cell lines. By contrast we show here that ceramide induces non-apoptotic killing of malignant cells from patients with B-chronic lymphocytic leukaemia (B-CLL) and of normal B lymphocytes. The protein phosphatase inhibitor okadaic acid readily induces apoptosis of B-CLL cells, indicating that this death pathway is fully functional in these cells. The ability of ceramide to activate the apoptotic protease caspase 3 in HL60 cells but not in B-CLL cells, as well as the lack of correlation of ceramide-mediated killing of different B-CLL isolates with expression of the apoptosis-regulating proteins bcl-2 and bax reinforce the conclusion that ceramide killing of B-CLL cells is by a non-apoptotic mechanism. Fludarabine treatment or γ-irradiation of B-CLL cells resulted in ceramide elevation and in killing by both apoptotic and non-apoptotic mechanisms, suggesting that a ceramide-triggered non-apoptotic mechanism may play a role in the killing of these cells. Therefore, the results here show that ceramide can induce either apoptotic or non-apoptotic death, depending on the cellular context. The inability of synthetic dihydroceramide to kill B-CLL cells or normal B lymphocytes suggests that non-apoptotic killing by ceramide is via interaction with a specific, but unidentified, cellular target.

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Acknowledgements

This research was supported in part by the Kay Kendall Leukaemia Fund. We thank Dr A Graham for advice on chromatographic analysis of ceramides.

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Authors and Affiliations

  1. Department of Hematology Royal Free and University College School of Medicine, Rowland Hill Street, London, NW3 2PF, UK

    Kamuran Mengubas, Fiona A Riordan, Christopher A Bravery, Atul B Mehta, A Victor Hoffbrand & R Gitendra Wickremasinghe

  2. Department of Histopathology Royal Free and University College School of Medicine, Rowland Hill Street, London, NW3 2PF, UK

    Jackie Lewin

  3. Hemophilia Centre, Royal Free and University College School of Medicine, Rowland Hill Street, London, NW3 2PF, UK

    Dale L Owens

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  1. Kamuran Mengubas
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Mengubas, K., Riordan, F., Bravery, C. et al. Ceramide-induced killing of normal and malignant human lymphocytes is by a non-apoptotic mechanism. Oncogene 18, 2499–2506 (1999). https://doi.org/10.1038/sj.onc.1202622

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