Attenuation of TNFSF10/TRAIL-induced apoptosis by an autophagic survival pathway involving TRAF2- and RIPK1/RIP1-mediated MAPK8/JNK activation

Abstract

Although it is known that tumor necrosis factor-related apoptosis-inducing ligand (TNFSF10/TRAIL) induces autophagy, the mechanism by which autophagy is activated by TNFSF10 is still elusive. In this report, we show evidence that TRAF2- and RIPK1-mediated MAPK8/JNK activation is required for TNFSF10-induced cytoprotective autophagy. TNFSF10 activated autophagy rapidly in cancer cell lines derived from lung, bladder and prostate tumors. Blocking autophagy with either pharmacological inhibitors or siRNAs targeting the key autophagy factors BECN1/Beclin 1 or ATG7 effectively increased TNFSF10-induced apoptotic cytotoxicity, substantiating a cytoprotective role for TNFSF10-induced autophagy. Blocking MAPK8 but not NFκB effectively blocked autophagy, suggesting that MAPK8 is the main pathway for TNFSF10-induced autophagy. In addition, blocking MAPK8 effectively inhibited degradation of BCL2L1/Bcl-xL and reduction of the autophagy-suppressing BCL2L1-BECN1complex. Knockdown of TRAF2 or RIPK1 effectively suppressed TNFSF10-induced MAPK8 activation and autophagy. Furthermore, suppressing autophagy inhibited expression of antiapoptosis factors BIRC2/cIAP1, BIRC3/cIAP2, XIAP and CFLAR/c-FLIP and increased the formation of TNFSF10-induced death-inducing signaling complex (DISC). These results reveal a critical role for the MAPK8 activation pathway through TRAF2 and RIPK1 for TNFSF10-induced autophagy that blunts apoptosis in cancer cells. Thus, suppression of MAPK8-mediated autophagy could be utilized for sensitizing cancer cells to therapy with TNFSF10.

ROS activates JNK-mediated autophagy to counteract apoptosis in mouse mesenchymal stem cells in vitro

“…Further, JNK inhibitor attenuated Bcl-2 reduction. While previous studies have shown that Bcl-2 phosphorylation can disrupt the Bcl-2/Beclin1 complex for autophagy activation [30] , we recently found that the JNKmediated degradation of Bcl-2 also leads to the induction of autophagy [31] . Thus, it is possible to conclude that JNKmediated Bcl-2 degradation results in Beclin1-mediated autophagy activation in ROS-treated MSCs.…”

“…In our study, we clearly demonstrate that H 2 O 2 induces autophagy in MSCs, including increased LC3-II expression, decreased p62 expression, and autophagic flux. Autophagy can mediate cell survival or death, depending on the cell type, environment and stimulation [31,38,39] . The role of ROS-induced autophagy in MSCs is unclear.…”

“…Previously, it was demonstrated that autophagy can be induced through the JNK-mediated phosphorylation or degradation of Bcl-2 and Bcl-xL, which attenuates the inhibition of Bcl-2 and Bcl-xL on Beclin-1 [30,31] . To investigate whether JNK is involved in autophagy induced by H 2 O 2 , cells were treated for different time periods, and the phosphorylation of JNK, the activated form of JNK, was detected by Western blot.…”

Acquired resistance to metformin in breast cancer cells triggers transcriptome reprogramming toward a degradome-related metastatic stem-like profile

“…[65][66][67][68] The antiapoptotic BCL2 family proteins, such as BCL2, bind beclin-1 (BECN1) to inhibit autophagy, and the dissociation of BCL2 family proteins from BECN1 promotes autophagy. [69][70][71] Because MCF-7 human breast carcinoma cells do not express caspase-3, earlier studies have shown that TNFSF10 induces autophagy in MCF-7 cells, and autophagy is protective against the cytotoxicity of TNFSF10 in these cells, 72 the prominent augmentation of TNFSF10 gene expression is accompanied by a severe inhibition of BCL2 (11-fold downregulation vs. metformin-naïve MCF-7 cells), which strongly suggests that the activation of protective autophagy plays a causative role in the acquisition of resistance to metformin. The metformin-refractory MCF-7/MET-R cells also activated (14-fold vs. metformin-naïve MCF-7 cells) the expression of TNFAIP2, which encodes tumor necrosis factor Table 1.…”

Cross-cancer profiling of molecular alterations within the human autophagy interaction network

“…TNFSF10 can trigger cell survival and proliferation through NFKB/nuclear factor kappa B and/or MAPK8 (mitogen-activated protein kinase 8)-mediated cytoprotective autophagy. 52 Further investigation of the TNFSF10/TRAIL-MAPK8-autophagy axis in alveolar ridge tumors may reveal a cell-type dependent role for autophagy in the pathogenesis of these rare but aggressive tumors.…”