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 (O-2(-)) concentration can abrogate Fas-mediated apoptosis In cells which are constitutively sensitive to Fas, Conversely, an O-2(-) concentration decrease is observed to sensitize cells which are naturally resistant to Fas signals, These observations suggest that intracellular O-2(-) 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.