Acrolein-induced cell death: a caspase-influenced decision between apoptosis and oncosis/necrosis.
Due to the dominating roles that caspases play in the apoptotic cascade, their activities appear to be a primary factor in the death pathway (apoptosis versus oncosis/necrosis) decision. In murine FL5.12 proB lymphocytes, the cellular consequences of acrolein treatment included a lack of typical apoptotic features in preference to oncosis/necrosis. Oncosis/necrosis was apparent by detection of a reduction in intracellular ATP concentration, increased plasma membrane leakage (measured by LDH release and flow cytometric detection of propidium iodide uptake) and morphological criteria. Analysis of acrolein-treated cell lysates or recombinant caspase enzymes showed overall dose-dependent decreases in caspase-3, -8 and -9 activities. In addition to acrolein's effect on intracellular caspases, it was also able to alter caspase-dependent apoptosis induced by secondary treatment with etoposide or following cytokine withdrawal. Acrolein at doses > or =20 microM circumvented etoposide or interleukin-3 withdrawal induced apoptosis. When acrolein was combined with mechlorethamine, another alkylating agent not dependent on caspases for its cell death signaling, necrosis was increased in a dose-dependent manner. Overall, these data suggest that caspase inhibition plays an important role in the cell death pathway decision, particularly with treatments dependent on the caspase cascade to induce apoptosis.
Kern
Julie C
JC
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712-1074, USA. jbratta@mail.utexas.edu
Kehrer
James P
JP
D000171:Acrolein / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D009336:Necrosis; D011994:Recombinant Proteins / Q000378:metabolism
D011994:Recombinant Proteins; D000171:Acrolein; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D020169:Caspases