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Blood, 1 November 2001, Vol. 98, No. 9, pp. 2828-2836
NEOPLASIA
Sphingosine 1-phosphate antagonizes apoptosis of human leukemia
cells by inhibiting release of cytochrome c and Smac/DIABLO
from mitochondria
Olivier Cuvillier and
Thierry Levade
From Inserm U466, Toulouse, France.
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- (TNF-), 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-, 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.
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