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1,25-Dihydroxyvitamin D₃ Inhibits Programmed Cell Death in HL-60 Cells by Activation of Sphingosine Kinase¹

Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, DC 20007

Sphingolipid breakdown products [ceramide, sphingosine, and sphingosine-1-phosphate (SPP)] are emerging as a new class of bioactive molecules. In agreement with previous studies, treatment of human promyelocytic leukemia HL-60 cells with 1-,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃] induced a transient increase of ceramide levels within 2 h, which then returned to basal levels within 8 h. In contrast, sphingosine kinase activity increased more slowly and reached maximal levels only after 20 h of exposure, leading to a concomitant increase in SPP level. Unlike treatments with cell-permeable ceramide analogues or sphingomyelinase, which induce apoptosis, 1,25-(OH)₂D₃ did not induce apoptosis, despite the early formation of ceramide. Moreover, prolonged treatment of HL-60 cells with 1,25-(OH)₂D₃ suppressed ceramide-induced apoptosis. There was a correlation between the time course and dose response of the activation of sphingosine kinase by 1,25-(OH)₂D₃ and the protection against apoptosis. In contrast, treatment with all-trans-retinoic acid neither stimulated sphingosine kinase activity nor protected cells from ceramide-induced apoptosis. Treatment with SPP protected HL-60 cells from ceramide-induced apoptosis, and N,N-dimethylsphingosine (DMS), a competitive inhibitor of sphingsoine kinase, prevented the survival effect of 1,25-(OH)₂D₃. The effect of DMS was counteracted by SPP, suggesting that SPP is a critical component of the cytoprotective effect of 1,25-(OH)₂D₃. Chelerythrine chloride, an inhibitor of protein kinase C, markedly reduced sphingosine kinase activity and the apoptosis-sparing effect of 1,25-(OH)₂D₃, and conversely, the tumor promoter 12-O-tetradecanoylphorbol-13-acetate not only suppressed ceramide-induced apoptosis but also stimulated sphingosine kinase activity. Moreover, the protective effect of 12-O-tetradecanoylphorbol-13-acetate was blocked by DMS. Collectively, our observations indicate that the cytoprotective effect of 1,25-(OH)₂D₃ is mediated by SPP, which is formed as a consequence of activation of sphingosine kinase.

¹ This work was supported by NIH Research Grants GM 43880 and CA61774.

² To whom requests for reprints should be addressed, at Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, 353 Basic Science Building, 3900 Reservoir Road NW, Washington, DC 20007. Phone: (202) 687-1432; Fax: (202) 687-0260.

Received 10/ 6/97. Accepted 3/ 4/98.

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