Attenuation of TNFSF10/TRAIL-induced apoptosis by an autophagic survival pathway involving TRAF2-and RIPK1/RIP1-mediated MAPK8/JNK activation
Attenuation of TNFSF10/TRAIL-induced apoptosis by an autophagic survival pathway involving TRAF2-and RIPK1/RIP1-mediated MAPK8/JNK activation
复制标题
DOI：
10.4161/auto.22145
复制
发表时间：
2012-12-01
期刊：
影响因子：
13.3
通讯作者：
Lin, Yong
中科院分区：
文献类型：
--
作者：
He, Weiyang;Wang, Qiong;Lin, Yong
尽管已知肿瘤坏死因子相关凋亡诱导配体（TNFSF 10/TRAIL）诱导自噬，但TNFSF 10激活自噬的机制仍不清楚。在这份报告中，我们证明TRAF 2和RIPK 1介导的MAPK 8/JNK激活是TNFSF 10诱导的细胞保护性自噬所必需的。TNFSF 10在源自肺、膀胱和前列腺肿瘤的癌细胞系中迅速激活自噬。用药理学抑制剂或靶向关键自噬因子BECN 1/Beclin 1或ATG 7的siRNA阻断自噬有效地增加了TNFSF 10诱导的凋亡细胞毒性，证实了TNFSF 10诱导的自噬的细胞保护作用。阻断MAPK 8而非NFkB有效地阻断了自噬，表明MAPK 8是TNFSF 10诱导的自噬的主要途径。此外，阻断MAPK 8可有效抑制BCL 2L 1/Bcl-xL的降解和自噬抑制BCL 2L 1-BECN 1复合物的减少。TRAF 2或RIPK 1的敲低有效地抑制了TNFSF 10诱导的MAPK 8活化和自噬。此外，抑制自噬抑制抗凋亡因子BIRC 2/cIAP 1、BIRC 3/cIAP 2、XIAP和CFLAR/c-FLIP的表达，并增加TNFSF 10诱导的死亡诱导信号复合物（DISC）的形成。这些结果揭示了MAPK 8活化途径通过TRAF 2和RIPK 1对TNFSF 10诱导的自噬的关键作用，该自噬减弱了癌细胞中的凋亡。因此，MAPK 8介导的自噬的抑制可用于使癌细胞对TNFSF 10治疗敏感。
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 NFkB 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.