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Chronic Myeloproliferative Disorders

Sphingosine kinase-1 is a downstream regulator of imatinib-induced apoptosis in chronic myeloid leukemia cells

Leukemia volume 22, pages 971–979 (2008)Cite this article

Abstract

We examined the involvement of sphingosine kinase-1 (SphK1), which governs the ceramide/sphingosine-1-phosphate balance, in susceptibility to imatinib of either sensitive or resistant chronic myeloid leukemia cells. Imatinib-sensitive LAMA84-s displayed marked SphK1 inhibition coupled with increased content of ceramide and decreased pro-survival sphingosine-1-phosphate. Conversely, no changes in the sphingolipid metabolism were observed in LAMA84-r treated with imatinib. Overcoming imatinib resistance in LAMA84-r with farnesyltransferase or MEK/ERK inhibitors as well as with cytosine arabinoside led to SphK1 inhibition. Overexpression of SphK1 in LAMA84-s cells impaired apoptosis and inhibited the effects of imatinib on caspase-3 activation, cytochrome c and Smac release from mitochondria through modulation of Bim, Bcl-xL and Mcl-1 expression. Pharmacological inhibition of SphK1 with F-12509a or its silencing by siRNA induced apoptosis of both imatinib-sensitive and -resistant cells, suggesting that SphK1 inhibition was critical for apoptosis signaling. We also show that imatinib-sensitive and -resistant primary cells from chronic myeloid leukemia patients can be successfully killed in vitro by the F-12509a inhibitor. These results uncover the involvement of SphK1 in regulating imatinib-induced apoptosis and establish that SphK1 is a downstream effector of the Bcr-Abl/Ras/ERK pathway inhibited by imatinib but upstream regulator of Bcl-2 family members.

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Acknowledgements

We thank Dr Wattenberg (Institute of Medical and Veterinary Science, Adelaide, South Australia, Australia) and Dr Buchdunger (Novartis, Basel, Switzerland) for generous gifts of reagents. This work was supported by Inserm, CNRS and Fondation pour la Recherche Médicale (to OC). EB and CM are recipients of the Ministère de l'Enseignement Supérieur et de la Recherche.

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Author notes

  1. D J Barnes

    Present address: Current address: Weatherall Institute of Molecular Medicine, Oxford, UK,

  2. J V Melo

    Present address: Current address: Institute of Medical and Veterinary Science, Adelaide, South Australia, Australia,

Authors and Affiliations

  1. CNRS, Institut de Pharmacologie et de Biologie Structurale, UMR5089, Toulouse, France

    E Bonhoure, C Martin, B Malavaud & O Cuvillier

  2. Inserm, U466, Toulouse, France

    E Bonhoure, A Lauret & O Cuvillier

  3. Université Toulouse III Paul Sabatier, Toulouse, France

    E Bonhoure, A Lauret, C Martin, B Malavaud & O Cuvillier

  4. Department of Haematology, Imperial College London, Hammersmith Hospital, London, UK

    D J Barnes & J V Melo

  5. Daiichi Sankyo Co. Ltd, Tokyo, Japan

    T Kohama

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Correspondence to O Cuvillier.

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

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Bonhoure, E., Lauret, A., Barnes, D. et al. Sphingosine kinase-1 is a downstream regulator of imatinib-induced apoptosis in chronic myeloid leukemia cells. Leukemia 22, 971–979 (2008). https://doi.org/10.1038/leu.2008.95

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