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1,25-Dihydroxyvitamin D3 protects human leukemic cells from tumor necrosis factor-induced apoptosis via inactivation of cytosolic phospholipase A2. 1998

Y L Wu, and X R Jiang, and D M Lillington, and P D Allen, and A C Newland, and S M Kelsey
Department of Hematology, St. Bartholomew's and The Royal London School of Medicine and Dentistry, University of London, 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 membrane, and (c) the up-regulation of cPLA2 mRNA with TNF. Furthermore, 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.

UI MeSH Term Description Entries
D007938 Leukemia A progressive, malignant disease of the blood-forming organs, characterized by distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemias were originally termed acute or chronic based on life expectancy but now are classified according to cellular maturity. Acute leukemias consist of predominately immature cells; chronic leukemias are composed of more mature cells. (From The Merck Manual, 2006) Leucocythaemia,Leucocythemia,Leucocythaemias,Leucocythemias,Leukemias
D010741 Phospholipases A Phospholipases that hydrolyze one of the acyl groups of phosphoglycerides or glycerophosphatidates.
D002117 Calcitriol The physiologically active form of vitamin D. It is formed primarily in the kidney by enzymatic hydroxylation of 25-hydroxycholecalciferol (CALCIFEDIOL). Its production is stimulated by low blood calcium levels and parathyroid hormone. Calcitriol increases intestinal absorption of calcium and phosphorus, and in concert with parathyroid hormone increases bone resorption. 1 alpha,25-Dihydroxycholecalciferol,1 alpha,25-Dihydroxyvitamin D3,1, 25-(OH)2D3,1,25(OH)2D3,1,25-Dihydroxycholecalciferol,1,25-Dihydroxyvitamin D3,1 alpha, 25-dihydroxy-20-epi-Vitamin D3,1,25(OH)2-20epi-D3,1,25-dihydroxy-20-epi-Vitamin D3,20-epi-1alpha,25-dihydroxycholecaliferol,Bocatriol,Calcijex,Calcitriol KyraMed,Calcitriol-Nefro,Decostriol,MC-1288,MC1288,Osteotriol,Renatriol,Rocaltrol,Silkis,Sitriol,Soltriol,Tirocal,1 alpha,25 Dihydroxyvitamin D3,1,25 Dihydroxycholecalciferol,1,25 Dihydroxyvitamin D3,1,25 dihydroxy 20 epi Vitamin D3,Calcitriol Nefro,D3, 1 alpha,25-Dihydroxyvitamin,D3, 1,25-Dihydroxyvitamin,D3, 1,25-dihydroxy-20-epi-Vitamin,KyraMed, Calcitriol,MC 1288
D002462 Cell Membrane The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells. Plasma Membrane,Cytoplasmic Membrane,Cell Membranes,Cytoplasmic Membranes,Membrane, Cell,Membrane, Cytoplasmic,Membrane, Plasma,Membranes, Cell,Membranes, Cytoplasmic,Membranes, Plasma,Plasma Membranes
D003513 Cycloheximide Antibiotic substance isolated from streptomycin-producing strains of Streptomyces griseus. It acts by inhibiting elongation during protein synthesis. Actidione,Cicloheximide
D003593 Cytoplasm The part of a cell that contains the CYTOSOL and small structures excluding the CELL NUCLEUS; MITOCHONDRIA; and large VACUOLES. (Glick, Glossary of Biochemistry and Molecular Biology, 1990) Protoplasm,Cytoplasms,Protoplasms
D003609 Dactinomycin A compound composed of a two CYCLIC PEPTIDES attached to a phenoxazine that is derived from STREPTOMYCES parvullus. It binds to DNA and inhibits RNA synthesis (transcription), with chain elongation more sensitive than initiation, termination, or release. As a result of impaired mRNA production, protein synthesis also declines after dactinomycin therapy. (From AMA Drug Evaluations Annual, 1993, p2015) Actinomycin,Actinomycin D,Meractinomycin,Cosmegen,Cosmegen Lyovac,Lyovac-Cosmegen,Lyovac Cosmegen,Lyovac, Cosmegen,LyovacCosmegen
D004790 Enzyme Induction An increase in the rate of synthesis of an enzyme due to the presence of an inducer which acts to derepress the gene responsible for enzyme synthesis. Induction, Enzyme
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D001692 Biological Transport The movement of materials (including biochemical substances and drugs) through a biological system at the cellular level. The transport can be across cell membranes and epithelial layers. It also can occur within intracellular compartments and extracellular compartments. Transport, Biological,Biologic Transport,Transport, Biologic

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