Superoxide anion is a natural inhibitor of FAS-mediated cell death.
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.
Clément
M V
MV
Department of Pathology, Harvard Medical School and Pathology Research, Boston, MA 02129, USA.
Stamenkovic
I
I
D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms; D002460:Cell Line; D004050:Ditiocarb / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008163:Luminescent Measurements; D008545:Melanoma; D012516:Osteosarcoma; D018384:Oxidative Stress; D010703:Phorbol Esters / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000494:pharmacology; D011994:Recombinant Proteins / Q000096:biosynthesis; D013481:Superoxides / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology; D001749:Urinary Bladder Neoplasms; D019014:fas Receptor / Q000096:biosynthesis / Q000502:physiology*
D000975:Antioxidants; D004791:Enzyme Inhibitors; D010703:Phorbol Esters; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D013481:Superoxides; D004050:Ditiocarb