Sphingosine 1-phosphate antagonizes apoptosis of human leukemia cells by inhibiting release of cytochrome c and Smac/DIABLO from mitochondria.
Sphingosine 1-phosphate (S-1P) has been implicated as a second messenger preventing apoptosis by counteracting activation of executioner caspases. Here it is reported that S-1P prevents apoptosis and executioner caspase-3 activation by inhibiting the translocation of cytochrome c and Smac/DIABLO from mitochondria to the cytosol induced by anti-Fas, tumor necrosis factor-alpha (TNF-alpha), serum deprivation, and cell-permeable ceramides in the human acute leukemia Jurkat, U937, and HL-60 cell lines. Furthermore, the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate, which stimulates sphingosine kinase, the enzyme responsible for S-1P production, also inhibits cytochrome c and Smac/DIABLO release. In contrast, dimethylsphingosine (DMS), a specific inhibitor of sphingosine kinase, sensitizes cells to cytochrome c and Smac/DIABLO release triggered by anti-Fas, TNF-alpha, serum deprivation, or ceramide. DMS-induced mitochondrial apoptogenic factor leakage can likewise be overcome by S-1P cotreatment. Hence, S-1P, likely generated through a protein kinase C- mediated activation of sphingosine kinase, inhibits the apoptotic cascade upstream of the release of the mitochondrial apoptogenic factors, cytochrome c, and Smac/DIABLO in human acute leukemia cells.
Cuvillier
O
O
Inserm U466, Toulouse, France. olivier.cuvillier@rangueil.inserm.fr
Levade
T
T
D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D002518:Ceramides / Q000494:pharmacology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D003574:Cytochrome c Group / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D007938:Leukemia / Q000473:pathology*; D008246:Lysophospholipids; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D020298:U937 Cells
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D002518:Ceramides; D016895:Culture Media, Serum-Free; D003574:Cytochrome c Group; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008246:Lysophospholipids; D024101:Mitochondrial Proteins; D018124:Receptors, Tumor Necrosis Factor; C060506:sphingosine 1-phosphate; C061800:N,N-dimethylsphingosine; D013110:Sphingosine; D013755:Tetradecanoylphorbol Acetate