Delayed oxidant-induced cell death involves activation of phospholipase A2.
Short-term (1 h) exposure of cells to a low steady-state concentration of H(2)O(2) causes no immediate cell death but apoptosis occurs several hours later. This delayed cell death may arise from activation of phospholipases, in particular phospholipase A2 (PLA2), which may destabilize lysosomal and mitochondrial membranes. Indeed, the secretory PLA2 (sPLA2) inhibitor 4-bromophenacyl bromide diminishes both delayed lysosomal rupture and apoptosis. Furthermore, sPLA2 activation by mellitin, or direct micro-injection of sPLA2, causes lysosomal rupture and apoptosis. Finally, B-cell leukemia/lymphoma 2 (Bcl-2) over-expression prevents oxidant-induced activation of PLA2, delayed lysosomal destabilization and apoptosis. This supports a causal association between PLA2 activation and delayed oxidant-induced cell death and suggests that Bcl-2 may suppress apoptosis by preventing PLA2 activation.
Zhao
M
M
Division of Pathology II, Faculty of Health Sciences, Linköping University, Sweden. ming.zhao@inr.liu.se
Brunk
U T
UT
Eaton
J W
JW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D015870:Gene Expression; D054501:Group II Phospholipases A2; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008555:Melitten / Q000494:pharmacology; D051379:Mice; D008845:Microinjections; D008856:Microscopy, Fluorescence; D016877:Oxidants / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D054467:Phospholipases A2; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
D016877:Oxidants; D019253:Proto-Oncogene Proteins c-bcl-2; D008555:Melitten; D006861:Hydrogen Peroxide; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2