JNK/SAPK activity is not sufficient for anticancer therapy-induced apoptosis involving CD95-L, trail and TNF-alpha

We report here that stress stimuli such as gamma-irradiation or the antican cer drug doxorubicin activate expression of the death-inducing ligands (DIL s) CD95-L, TNF-alpha and TRAIL. Apoptosis induced by gamma-irradiation or d oxorubicin engages a FADD- and caspase-dependent apoptosis pathway which is inhibited by dominant negative FADD or the caspase inhibitor zVAD. zVAD di d not prevent activity of JNK/SAPKs in response to doxorubicin suggesting t hat JNK/SAPK activity is independent of death receptor triggering during ce llular stress-induced apoptosis. In addition, JNK/SAPKs remained activated by doxorubicin in resistant cell lines in which cleavage of caspases and ap optosis was not observed. These data uncouple JNK/SAPK activation and apopt osis signaling and indicate that cellular stress-induced apoptosis involves signaling via DILs which is paralleled by activation of JNK/SAPKs. Activat ion of these kinases may contribute e.g., to the expression of molecules in volved in apoptosis but is not sufficient for induction of the apoptosis pr ogram following cellular stress. (C) 1999 Wiley-Liss, Inc.