Common regulation of apoptosis signaling induced by CD95 and the DNA-damaging stimuli etoposide and gamma-radiation downstream from caspase-8 activation

The death receptor CD95 (APO-1/Fas), the anticancer drug etoposide, and gam ma-radiation induce apoptosis in the human T cell line Jurkat. Variant clon es selected for resistance to CD95-induced apoptosis proved cross-resistant to etoposide- and radiation-induced apoptosis, suggesting that the apoptos is pathways induced by these distinct stimuli have critical component(s) in common. The pathways do not converge at the level of CD95 ligation or casp ase-8 signaling. Whereas caspase-8 function was required for CD95-mediated cytochrome c release, effector caspase activation, and apoptosis, these res ponses were unaffected in etoposide-treated and irradiated cells when caspa se-8 was inhibited by FLIPL. Both effector caspase processing and cytochrom e c release were inhibited in the resistant variant cells as well as in Bcl -2 transfectants, suggesting that, in Jurkat cells, the apoptosis signaling pathways activated by CD95, etoposide, and gamma-radiation are under commo n mitochondrial control. All three stimuli induced ceramide production in w ild-type cells, but not in resistant variant cells. Exogenous ceramide bypa ssed apoptosis resistance in the variant cells, but not in Bcl-2-transfecte d cells, suggesting that apoptosis signaling induced by CD95, etoposide, an d gamma-radiation is subject to common regulation at a level different from that targeted by Bcl-2.