Molecular ordering of ROS production, mitochondrial changes, and caspase activation during sodium salicylate-induced apoptosis.
Salicylates and nonsteroidal anti-inflammatory drugs (NSAIDs) induce apoptosis in a variety of cancer cells, including those of colon, prostate, breast, and leukemia. We examined the effects of sodium salicylate (NaSal) on reactive oxygen species (ROS) production and the association of these effects with apoptotic tumor cell death. We demonstrate that NaSal mediates ROS production followed by a decrease in mitochondrial membrane potential (deltapsi(m)), release of cytochrome c, and activation of caspase-9 and caspase-3. However, expression of Bcl-2 or Bcl-x(L) prevents ROS production and subsequent loss of deltapsi(m), thereby inhibiting apoptotic cell death. The presence of ROS scavengers and an inhibitor of NADPH oxidase or expression of a dominant negative form of Rac1 blocks ROS production, deltapsi(m) collapse, and the subsequent activation of caspases. These observations indicate that NaSal mediates ROS production critical in the triggering of apoptotic tumor cell death through a Rac1-NADPH oxidase-dependent pathway. Our data collectively imply that NaSal-induced ROS are key mediators of deltapsi(m) collapse, which leads to the release of cytochrome c followed by caspase activation, culminating in tumor apoptosis.
Chung
Young Mee
YM
Division of Molecular Life Sciences and Center for Cell Signaling Research, Ewha Womans University, Seoul, South Korea.
Bae
Yun Soo
YS
Lee
Soo Young
SY
D000230:Adenocarcinoma; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D003110:Colonic Neoplasms; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation; D015870:Gene Expression; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000648:ultrastructure*; D019255:NADPH Oxidases / Q000378:metabolism; D009369:Neoplasms / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012980:Sodium Salicylate / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000473:pathology; D014162:Transfection; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein; D020830:rac1 GTP-Binding Protein / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; C494811:BCL2L1 protein, human; D003574:Cytochrome c Group; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051020:bcl-X Protein; D019255:NADPH Oxidases; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D020830:rac1 GTP-Binding Protein; D012980:Sodium Salicylate