Specific dual effect of cycloheximide on B lymphocyte apoptosis: involvement of CPP32/caspase-3.
Cycloheximide (CHX) is known to stimulate or to prevent apoptosis, according to the cell type used. We found that CHX, in a dose-dependent way, exerted the two opposite effects in B lymphocytes. CHXhigh (2.5 microg/mL) inhibited protein synthesis (>90%) and greatly increased B cell apoptosis but failed to prevent apoptosis induction by dexamethasone (DEX) or dibutyryl-cAMP (dbcAMP), which is in opposition with CHX activity in thymocytes. On the contrary, CHXlow (0.05 microg/mL), modestly inhibited protein synthesis (<15%) and reduced spontaneous as well as drug-induced apoptosis and further augmented the protection conferred by interleukin-4 or lipopolysaccharide. To examine the role of caspases in CHX effects, we used the broad spectrum peptide caspase inhibitor Z-VAD-fmk: it totally abrogated spontaneous as well as drug- and CHXhigh-induced cell death. Apoptosis was associated with CPP32/caspase-3 activation, since cleavage of CPP32/caspase-3 and caspase-3 activity were increased by DEX, dbcAMP as well as by CHXhigh treatment. Meanwhile, caspase-3 activity was reduced by CHXlow treatment. Therefore, CHX exerts opposite effects on B lymphocyte apoptosis which are associated with a dual action on caspase-3 activation.
Institut de Biochimie, CNRS ERS 0571, Université Paris-Sud, Orsay, France. christophe.lemaire@bbmpc.u-psud.fr
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D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism* / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D010452:Peptide Biosynthesis / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology
D011500:Protein Synthesis Inhibitors; D003513:Cycloheximide; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases