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DR5-Cbl-b/c-Cbl-TRAF2 复合物通过促进 TRAF2 介导的半胱天冬酶-8 多泛素化来抑制胃癌细胞中 TRAIL 诱导的细胞凋亡。

DR5-Cbl-b/c-Cbl-TRAF2 complex inhibits TRAIL-induced apoptosis by promoting TRAF2-mediated polyubiquitination of caspase-8 in gastric cancer cells.

机构信息

Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.

Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China.

出版信息

Mol Oncol. 2017 Dec;11(12):1733-1751. doi: 10.1002/1878-0261.12140. Epub 2017 Oct 27.

DOI:10.1002/1878-0261.12140
PMID:28972304
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5709619/
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.

摘要

泛素化的胱天蛋白酶-8 调节肿瘤细胞中 TNF 相关凋亡诱导配体（TRAIL）的敏感性，并且前配体组装复合物在胱天蛋白酶-8 的多泛素化中发挥作用。然而，这种复合物是否存在于胃癌细胞中及其在 TRAIL 触发的细胞凋亡中的作用尚不清楚。在这项研究中，DR5、卡斯蒂亚斯 B 细胞淋巴瘤-b（Cbl-b）/c-Cbl 和 TRAF2 在 TRAIL 耐药的胃癌细胞中形成复合物，Cbl-b 和 c-Cbl 是将 DR5 和 TRAF2 连接起来的关键衔接蛋白。用 TRAIL 处理诱导胱天蛋白酶-8 易位到 DR5-Cbl-b/c-Cbl-TRAF2 复合物中与 TRAF2 相互作用，然后介导胱天蛋白酶-8 的 K48 连接的多泛素化。蛋白酶体抑制剂硼替佐米显著增加了 TRAIL 激活的胱天蛋白酶-8 的 p43/41 产物，表明胱天蛋白酶-8 的蛋白酶体降解。此外，TRAF2 的敲低阻止了胱天蛋白酶-8 的多泛素化，从而增加了 TRAIL 的敏感性。此外，抑制 Cbl-b 或 c-Cbl 的表达和过表达 miR-141 靶向 Cbl-b 和 c-Cbl 部分通过抑制 TRAF2 和胱天蛋白酶-8 之间的相互作用以及随后胱天蛋白酶-8 的多泛素化来逆转 TRAIL 耐药性。这些结果表明，DR5-Cbl-b/c-Cbl-TRAF2 复合物通过促进 TRAF2 介导的胱天蛋白酶-8 的多泛素化来抑制胃癌细胞中 TRAIL 诱导的细胞凋亡。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e80f/5709619/29088673c526/MOL2-11-1733-g010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e80f/5709619/29088673c526/MOL2-11-1733-g010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e80f/5709619/8b493b695b95/MOL2-11-1733-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e80f/5709619/cc239d84a587/MOL2-11-1733-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e80f/5709619/33203d47c5cd/MOL2-11-1733-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e80f/5709619/29088673c526/MOL2-11-1733-g010.jpg

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