Apoptosis induced by inhibitors of the plasma membrane NADH-oxidase involves Bcl-2 and calcineurin.
Activation of the plasma membrane NADH-oxidoreductase (PMOR) system by addition of growth factors or extracellular electron acceptors stimulates cellular proliferation. We now show that the vanilloids capsaicin, dihydrocapsaicin, and resiniferatoxin are inhibitors of the NADH-oxidase activity of the PMOR system and that both these and two previously identified PMOR inhibitors (chloroquine and retinoic acid) induce apoptosis in human B-cell and mouse myeloid cell lines. At the optimal concentration, PMOR inhibitors can induce between 50 and 70% of apoptosis in mouse myeloid and human B-cell lines within 8-12 h, provided these cell lines do not express Bcl-2. The immunosuppressants cyclosporin A and fujimycin (tacrolimus) inhibit PMOR inhibitor-induced apoptosis. By using combinations of these immunosuppressants and excess amounts of their nonimmunosuppressive analogues, we demonstrate that in human B-cell lines the Bcl-2-sensitive apoptotic pathway triggered by PMOR inhibitors involves signaling through the protein phosphatase calcineurin. We suggest that the PMOR system is a redox sensor that can, depending on the ambient redox environment and the availability of growth factors, regulate plasma membrane calcium fluxes and signal for apoptosis through calcineurin. Bcl-2, a protein that is thought to inhibit apoptosis by regulating reactive oxygen species and calcium fluxes in the cell, inhibits this apoptotic pathway.
Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia. Ernst Wolvetang@med.monash.edu.au
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000378:metabolism*; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002460:Cell Line; D004224:Diterpenes / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*
D002148:Calmodulin-Binding Proteins; D004224:Diterpenes; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D009097:Multienzyme Complexes; D019253:Proto-Oncogene Proteins c-bcl-2; C024353:resiniferatoxin; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D002211:Capsaicin; C012906:dihydrocapsaicin