Constitutive and activation-inducible cyclooxygenase-2 expression enhances survival of chronic lymphocytic leukemia B cells.
We recently reported that activated normal human B lymphocytes express Cox-2. These findings prompted us to evaluate whether human B-CLL cells express Cox-2 and synthesize prostaglandins. In contrast to naive human B cells, B-CLL cells constitutively expressed Cox-2 protein and produced PGE2, PGF2alpha, and TXA2. Elevated Cox-2 expression was seen in a subgroup of B-CLL cells that exhibit poor prognostic factors, including unmutated variable heavy chain status and increased CD38 expression. Furthermore, stimulation of B-CLL cells with CD40 ligand plus TNFalpha increased Cox-2 levels. The role of Cox-2 in promoting B-CLL survival was investigated using nonselective and selective Cox-2 inhibitors. Significant reductions in B-CLL survival occurred following Cox-2 inhibition. These new findings support that constitutive Cox-2 expression in B-CLL cells promotes their survival and possibly their expansion in vivo. It will therefore be important to evaluate drugs that inhibit Cox-2 as potential therapeutic agents in B-CLL in vivo.
Ryan
Elizabeth P
EP
Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Pollock
Stephen J
SJ
Kaur
Kuljeet
K
Felgar
Raymond E
RE
Bernstein
Steven H
SH
Chiorazzi
Nicholas
N
Phipps
Richard P
RP
D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology; D048708:Cell Growth Processes / Q000502:physiology; D051545:Cyclooxygenase 1 / Q000276:immunology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015237:Dinoprost / Q000276:immunology; D015232:Dinoprostone / Q000276:immunology; D004789:Enzyme Activation; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D007150:Immunohistochemistry; D007213:Indomethacin / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D009578:Nitrobenzenes / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D013928:Thromboxane A2 / Q000276:immunology
C501048:3-(4-methylsulfonylphenyl)-4-phenyl-5-trifluoromethylisoxazole; D052246:Cyclooxygenase 2 Inhibitors; D007143:Immunoglobulin Heavy Chains; D007555:Isoxazoles; D009578:Nitrobenzenes; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C090859:1-((4-methylsulfonyl)phenyl)-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole; D013928:Thromboxane A2; D015237:Dinoprost; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D007213:Indomethacin