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1,25-Dihydroxyvitamin D₃ Protects Human Leukemic Cells from Tumor Necrosis Factor-induced Apoptosis via Inactivation of Cytosolic Phospholipase A₂

Departments of Hematology [Y-L. W., X-R. J., P. D. A., A. C. N., S. M. K.] and Medical Oncology [D. M. L.], St. Bartholomew's and The Royal London School of Medicine and Dentistry, University of London, London E1 2AD, United Kingdom

The mechanism by which tumor necrosis factor (TNF) induces death of cancer cells appears to involve the activation of cytosolic phospholipase A₂ (cPLA₂). U937 human leukemic cells treated with 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃; 10^-8 M] become resistant to TNF, an effect that is independent of cell cycle status and expression of TNF receptors or BCL-2. In this study, TNF produced a dose- and time-dependent enhancement of [³H]arachidonic acid release in U937 cells. The amount of [³H]arachidonic acid release was positively associated with TNF-induced apoptosis. Both immunofluorescence microscopy and Western blotting of cell subcompartments demonstrated translocation of cPLA₂ from the cytosol to the cell membrane in response to TNF. In addition, TNF up-regulated expression of cPLA₂ mRNA. An antisense oligonucleotide to cPLA₂ and the cPLA₂ inhibitor 4-bromophenacyl bromide significantly inhibited TNF-induced cytotoxicity. Prior incubation of cells with 1,25(OH)₂D₃ significantly inhibited (a) TNF-induced [³H]arachidonic acid release and apoptosis, (b) TNF-induced translocation of cPLA₂ to the thermore, the inhibitory effect of 1,25(OH)₂D₃ was not reversed by inhibitors of transcription or translation. The data suggest that activation of cPLA₂ is involved in TNF-induced apoptosis of leukemic cells. 1,25(OH)₂D₃ directly inhibits cPLA₂ translocation and mRNA up-regulation induced by TNF. Disruption of cPLA₂ activation may represent a possible mechanism whereby leukemic cells can become resistant to TNF-mediated killing.

¹ To whom requests for reprints should be addressed, at Department of Hematology, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Turner St., London E1 2AD, United Kingdom. Phone: (44-171) 377-7178; Fax: (44-171) 377-7016; E-mail: S.M.Kelsey@mds.qmw.ac.UK.

Received 9/15/97. Accepted 12/15/97.

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