The superoxide dismutase inhibitor diethyldithiocarbamate has antagonistic effects on apoptosis by triggering both cytochrome c release and caspase inhibition.
Tumor necrosis factor-alpha (TNF-alpha) and etoposide both trigger a large and rapid production of reactive oxygen species (ROS) in HeLa cells. This occurs before translocations of the proapoptotic Bax and cytochrome c proteins, the loss of mitochondrial membrane potential (DeltaPsim), and apoptosis. We have used diethyldithiocarbamate (DDC), a well-known inhibitor of Cu, Zn superoxide dismutase to study the role of ROS in this system. We report that DDC strongly inhibits caspase activation, loss of DeltaPsim, and cell death induced by TNF-alpha or etoposide. Surprisingly, DDC does not inhibit Bax and cytochrome c translocations. On the contrary, we have observed that DDC can trigger the translocations of these proteins by itself, without altering DeltaPsim. Here, we report that DDC has at least two antagonistic apoptosis regulation functions. First, DDC triggers ROS-dependent Bax and cytochrome c translocations, which are potentially proapoptotic, and second, DDC inhibits caspase activation and activity, loss of DeltaPsim, and cell death, in a ROS-independent manner. Our results suggest an interesting model in which ROS-dependent Bax and cytochrome c translocations can be studied without interference from later apoptotic events.
Dumay
Anne
A
Université de Versailles/St. Quentin-en-Yvelines, CNRS FRE-2445, Laboratoire de Génétique et Biologie cellulaire, Versailles, France.
Rincheval
Vincent
V
Trotot
Pascale
P
Mignotte
Bernard
B
Vayssière
Jean-Luc
JL
D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism*; D004050:Ditiocarb / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D010084:Oxidation-Reduction / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D004050:Ditiocarb; D013482:Superoxide Dismutase; D020169:Caspases