Staphylococcus aureus alpha-toxin-induced cell death: predominant necrosis despite apoptotic caspase activation.
Recent data suggest that alpha-toxin, the major hemolysin of Staphylococcus aureus, induces cell death via the classical apoptotic pathway. Here we demonstrate, however, that although zVAD-fmk or overexpression of Bcl-2 completely abrogated caspase activation and internucleosomal DNA fragmentation, they did not significantly affect alpha-toxin-induced death of Jurkat T or MCF-7 breast carcinoma cells. Caspase inhibition had also no effect on alpha-toxin-induced lactate dehydrogenase release and ATP depletion. Furthermore, whereas early assessment of apoptosis induction by CD95 resulted solely in the generation of cells positive for active caspases that were, however, not yet permeable for propidium iodide, a substantial proportion of alpha-toxin-treated cells were positive for both active caspases and PI. Finally, electron microscopy demonstrated that even in the presence of active caspases, alpha-toxin-treated cells displayed a necrotic morphology characterized by cell swelling and cytoplasmic vacuolation. Together, our data suggest that alpha-toxin-induced cell death proceeds even in the presence of activated caspases, at least partially, in a caspase-independent, necrotic-like manner.
Essmann
F
F
Institute of Molecular Medicine, University of Düsseldorf, Germany.
Bantel
H
H
Totzke
G
G
Engels
I H
IH
Sinha
B
B
Schulze-Osthoff
K
K
Jänicke
R U
RU
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006460:Hemolysin Proteins / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D019169:Jurkat Cells / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008854:Microscopy, Electron; D008954:Models, Biological; D008970:Molecular Weight; D009336:Necrosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013211:Staphylococcus aureus / Q000472:pathogenicity*; D019014:fas Receptor / Q000187:drug effects / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; D000906:Antibodies; D001427:Bacterial Toxins; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D006460:Hemolysin Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor; C021091:staphylococcal alpha-toxin; D020169:Caspases