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Superoxide anion is a natural inhibitor of FAS-mediated cell death.
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The cell surface receptor Fas is a major trigger of apoptosis. However, expression of the Fas receptor in many tumor cell types does not correlate with sensitivity to Fas-mediated cell death. Because a prooxidant state is a common feature of tumor cells, we examined the role of intracellular reactive oxygen intermediates in the regulation of Fas-mediated cytotoxicity. Our results show that an oxidative stress induced by increasing the intracellular superoxide anion (O2-) concentration can abrogate Fas-mediated apoptosis in cells which are constitutively sensitive to Fas. Conversely, an O2- concentration decrease is observed to sensitize cells which are naturally resistant to Fas signals. These observations suggest that intracellular O2- may play a key role in regulating cell sensitivity to a potentially lethal signal and provide tumor cells with a natural, inducible mechanism of resistance to Fas-mediated apoptosis.
Antigens, CD95/biosynthesis, Antigens, CD95/physiology, Antioxidants/pharmacology, Apoptosis/drug effects, Bone Neoplasms, Cell Line, Chemiluminescent Measurements, Ditiocarb/pharmacology, Enzyme Inhibitors/pharmacology, Humans, Kinetics, Melanoma, Osteosarcoma, Oxidative Stress, Phorbol Esters/pharmacology, Reactive Oxygen Species/pharmacology, Recombinant Proteins/biosynthesis, Superoxides/metabolism, Transfection, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha/biosynthesis, Tumor Necrosis Factor-alpha/physiology, Urinary Bladder Neoplasms
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