DR5-Cbl-b/c-Cbl-TRAF2 Complex Inhibits TRAIL-induced Apoptosis by Promoting TRAF2-mediated Polyubiquitination of Caspase-8 in Gastric Cancer Cells

Overview

Journal Mol Oncol

Specialties Molecular Biology
Oncology

Date 2017 Oct 4

PMID 28972304

Citations 16

Authors

Ling Xu

Ye Zhang

Xiujuan Qu

Xiaofang Che

Tianshu Guo

Ce Li

Rui Ma

Yibo Fan

Yanju Ma

Kezuo Hou

Danni Li

Xuejun Hu

Bofang Liu

Ruoxi Yu

Hongfei Yan

Jing Gong

Yunpeng Liu

Affiliations

Soon will be listed here.

Abstract

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, DR5, casitas B-lineage lymphoma-b (Cbl-b)/c-Cbl, and TRAF2 formed a complex in TRAIL-resistant gastric cancer cells, and Cbl-b and c-Cbl were the critical adaptors linking DR5 and TRAF2. Treatment with TRAIL induced caspase-8 translocation into the DR5-Cbl-b/c-Cbl-TRAF2 complex to interact with TRAF2, 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, TRAF2 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 TRAF2 and caspase-8 and the subsequent polyubiquitination of caspase-8. These results indicate that the DR5-Cbl-b/c-Cbl-TRAF2 complex inhibited TRAIL-induced apoptosis by promoting TRAF2-mediated polyubiquitination of caspase-8 in gastric cancer cells.

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