Attenuation Of TRAIL-induced Apoptosis By An Autophagic Survival Pathway Involving TRAF2-and RIP1-mediated JNK Activation

Although it is known that tumor necrosis factor-relatedapoptosis-inducing ligand (TRAIL) induces autophagy, the mechanism bywhich autophagy is activated by TRAIL is still elusive. In this report, weshow evidence that TRAF2-and RIP1-mediated JNK activation is requiredfor TRAIL-induced cytoprotective autophagy. TRAIL activated autophagyrapidly in cancer cell lines derived from lung, bladder and prostate tumors.Blocking autophagy with either pharmacological inhibitors or siRNAstargeting the key autophagy factors Beclin1or ATG7effectively increasedTRAIL-induced apoptotic cytotoxicity, substantiating a cytoprotective rolefor TRAIL induced autophagy.Blocking JNK but not NF-kB effectively blocked autophagy,suggesting that JNK is the main pathway for TRAIL-induced autophagy. Inaddition, blocking JNK effectively inhibited degradation of Bcl-xl andreduction of the autophagy-suppressing Bcl-xl–Beclin-1complex.Knockdown of TRAF2or RIP effectively suppressed TNFSF10-inducedJNK activation and autophagy. Furthermore, suppressing autophagyinhibited expression of antiapoptosis factors cIAP1, cIAP2, XIAP andc-FLIP and increased the formation of TRAIL-induced death-inducing signaling complex (DISC). These results reveal a critical role for the JNKactivation pathway through TRAF2and RIP1for TRAIL-inducedautophagy that blunts apoptosis in cancer cells. Thus, suppression ofJNK-mediated autophagy could be utilized for sensitizing cancer cells totherapy with TRAIL.