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 pr eventing apoptosis by counteracting activation of executioner caspases. Her e it is reported that S-1P prevents apoptosis and executioner caspase-3 act ivation by inhibiting the translocation of cytochrome c and Smac/DIABLO fro m mitochondria to the cytosol induced by anti-Fas, tumor necrosis factor-al pha (TNF-alpha), serum deprivation, and cell-permeable ceramides in the hum an acute leukemia Jurkat, U937, and HL-60 cell lines. Furthermore, the tumo r promoter 12-O-tetradecanoyl-phorbol-13-acetate, which stimulates sphingos ine kinase, the enzyme responsible for S-1P production, also inhibits cytoc hrome 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 lik ewise be overcome by S-1P cotreatment. Hence, S-1P, likely generated throug h a protein kinase C-mediated activation of sphingosine kinase, inhibits th e apoptotic cascade upstream of the release of the mitochondrial apoptogeni c factors, cytochrome c, and Smac/DIABLO in human acute leukemia cells. (C) 2001 by The American Society of Hematology.