Open AccessDR 5‐Cbl‐b/c‐Cbl‐ TRAF 2 complex inhibits TRAIL ‐induced apoptosis by promoting TRAF 2‐mediated polyubiquitination of caspase‐8 in gastric cancer cells
Author(s) -
Xu Ling,
Zhang Ye,
Qu Xiujuan,
Che Xiaofang,
Guo Tianshu,
Li Ce,
Ma Rui,
Fan Yibo,
Ma Yanju,
Hou Kezuo,
Li Danni,
Hu Xuejun,
Liu Bofang,
Yu Ruoxi,
Yan Hongfei,
Gong Jing,
Liu Yunpeng
Publication year - 2017
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12140
Subject(s) - ubiquitin , traf2 , apoptosis , caspase 8 , chemistry , ubiquitin ligase , cancer cell , deubiquitinating enzyme , microbiology and biotechnology , caspase 9 , proteasome , xiap , caspase 3 , caspase , cancer research , biology , cancer , biochemistry , programmed cell death , genetics , tumor necrosis factor receptor , gene
Ubiquitination of caspase‐8 regulates TNF‐related apoptosis‐inducing ligand ( TRAIL ) sensitivity in cancer cells, and the preligand assembly complex plays a role in caspase‐8 polyubiquitination. However, whether such a complex exists in gastric cancer cells and its role in TRAIL ‐triggered apoptosis is unclear. In this study, DR 5, casitas B‐lineage lymphoma‐b (Cbl‐b)/c‐Cbl, and TRAF 2 formed a complex in TRAIL ‐resistant gastric cancer cells, and Cbl‐b and c‐Cbl were the critical adaptors linking DR 5 and TRAF 2. Treatment with TRAIL induced caspase‐8 translocation into the DR 5‐Cbl‐b/c‐Cbl‐ TRAF 2 complex to interact with TRAF 2, which then mediated the K48‐linked polyubiquitination of caspase‐8. The proteasome inhibitor bortezomib markedly enriched the p43/41 products of caspase‐8 activated by TRAIL , indicating proteasomal degradation of caspase‐8. Moreover, TRAF 2 knockdown prevented the polyubiquitination of caspase‐8 and thus increased TRAIL sensitivity. In addition, the inhibition of Cbl‐b or c‐Cbl expression and overexpression of miR‐141 targeting Cbl‐b and c‐Cbl partially reversed TRAIL resistance by inhibiting the interaction between TRAF 2 and caspase‐8 and the subsequent polyubiquitination of caspase‐8. These results indicate that the DR 5‐Cbl‐b/c‐Cbl‐ TRAF 2 complex inhibited TRAIL ‐induced apoptosis by promoting TRAF 2‐mediated polyubiquitination of caspase‐8 in gastric cancer cells.