Oxysterol-induced cell death in human leukemic T-cells correlates with oxysterol binding protein occupancy and is independent of glucocorticoid-induced apoptosis.
In eukaryotic cells oxysterols inhibit cholesterol biosynthesis and cell growth. A potent oxysterol, 25-hydroxycholesterol, was used to investigate the biological effects of oxysterols on three clonal lines of either glucocorticoid-sensitive or -resistant CEM cells, human leukemic T-lymphocytes. In addition, the glucocorticoid sensitivity of an oxysterol-resistant CEM cell line was tested. Oxysterols blocked growth and caused the lysis of cells regardless of their glucocorticoid response. All cells studied herein possessed an oxysterol binding protein with high affinity for 25-hydroxycholesterol. For all clones grown in serum-free medium, the half-maximal cytolytic concentration of 25-hydroxycholesterol (20-40 nM) correlated with its affinity (Kd = approximately 31 nM) for this oxysterol binding protein. Both cholesterol and mevalonate reversed 25-hydroxycholesterol cytotoxicity; 3-6 microM cholesterol or 0.1 mM mevalonate decreased 60 nM 25-hydroxycholesterol cytotoxicity by 50%. This cholesterol or mevalonate reversal appeared possible even after several days of 60 nM oxysterol treatment. The protective effect of cholesterol could be overcome by increasing 25-hydroxycholesterol concentrations. Cholesterol and mevalonate did not prevent glucocorticoid-mediated lymphocytolysis. Furthermore, the oxysterol-resistant line was sensitive to dexamethasone lysis. These data support the hypothesis that oxysterols and glucocorticoids act independently to block the growth of human leukemic lymphoblasts.
Bakos
J T
JT
University of Texas Medical Branch, Department of Human Biological Chemistry and Genetics, Galveston 77555.
Johnson
B H
BH
Thompson
E B
EB
D017209:Apoptosis / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects*; D002784:Cholesterol / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology*; D006131:Growth Inhibitors; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D066298:In Vitro Techniques; D008798:Mevalonic Acid / Q000494:pharmacology; D011987:Receptors, Steroid / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000098825:Oxysterol Binding Proteins
D005938:Glucocorticoids; D006131:Growth Inhibitors; D006888:Hydroxycholesterols; D011987:Receptors, Steroid; D000098825:Oxysterol Binding Proteins; C007997:25-hydroxycholesterol; D002784:Cholesterol; D008798:Mevalonic Acid