Abstract
We examined the involvement of sphingosine kinase-1, a critical regulator of the sphingolipid balance, in susceptibility to antineoplastic agents of either sensitive or multidrug-resistant acute myeloid leukemia cells. Contrary to parental HL-60 cells, doxorubicin and etoposide failed to trigger apoptosis in chemoresistant HL-60/Doxo and HL-60/VP16 cells overexpressing MRP1 and MDR1, respectively. Chemosensitive HL-60 cells displayed sphingosine kinase-1 inhibition coupled with ceramide generation. In contrast, chemoresistant HL-60/Doxo and HL-60/VP16 had sustained sphingosine kinase-1 activity and did not produce ceramide during treatment. Enforced expression of sphingosine kinase-1 in chemosensitive HL-60 cells resulted in marked inhibition of apoptosis that was mediated by blockade of mitochondrial cytochrome c efflux hence suggesting a control of apoptosis at the premitochondrial level. Incubation with cell-permeable ceramide of chemoresistant cells led to a sphingosine kinase-1 inhibition and apoptosis both prevented by sphingosine kinase-1 overexpression. Furthermore, F-12509a, a new sphingosine kinase inhibitor, led to ceramide accumulation, decrease in sphingosine 1-phosphate content and caused apoptosis equally in chemosensitive and chemoresistant cell lines that is inhibited by adding sphingosine 1-phosphate or overexpressing sphingosine kinase-1. F-12509a induced classical apoptosis hallmarks namely nuclear fragmentation, caspase-3 cleavage as well as downregulation of antiapoptotic XIAP, and release of cytochrome c and SMAC/Diablo.
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Acknowledgements
We thank Dr Brian Wattenberg (Hanson Institute, Institute of Medical and Veterinary Science, Adelaide, Australia) for the plasmids encoding FLAG epitope-tagged wild-type hSphK1 and Gly82 → Asp hSphK1. Supported by Inserm, La Ligue Nationale Contre le Cancer ‘Comité Tarn et Garonne’ AO 2002, and Paul Sabatier University. EB and DP are recipients of the Ministère de l'Enseignement Supérieur et de la Recherche (PhD and Post-doctoral fellowships, respectively).
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Bonhoure, E., Pchejetski, D., Aouali, N. et al. Overcoming MDR-associated chemoresistance in HL-60 acute myeloid leukemia cells by targeting shingosine kinase-1. Leukemia 20, 95–102 (2006). https://doi.org/10.1038/sj.leu.2404023
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DOI: https://doi.org/10.1038/sj.leu.2404023
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