The TNF-related apoptosis-inducing ligand (TRAIL) apoptotic pathway has emerged as a therapeutic target for the treatment of cancer. However, clinical trials have proven that the vast majority of human cancers are resistant to TRAIL apoptotic pathway- targeted therapies. We show that A20-mediated ubiquitination inhibits caspase-8 cleavage and TRAIL-induced apoptosis in glioblastoma through 2 signaling complexes. A20 is highly expressed in glioblastomas and, together with the death receptor 5 and receptor-interacting protein 1, forms a plasma membrane-bound preligand assembly complex under physiologic conditions. Treatment with TRAIL leads to the recruitment of caspase-8 to the plasma membrane-bound preligand assembly complex for the assembly of a death-inducing signaling complex. In the death-inducing signaling complex, the C-terminal zinc finger (Znf) domain of the A20 ubiquitin ligase mediates receptor-interacting protein 1 polyubiquitination through lysine-63-linked polyubiquitin chains, which bind to the caspase-8 protease domain and inhibit caspase-8 dimerization, cleavage, and the initiation of TRAIL-induced apoptosis in glioblastoma-derived cell lines and tumor-initiating cells. SIGNIFICANCE: These results identify A20 E3 ligase as a therapeutic target whose inhibition can overcome TNF-related apoptosis-inducing ligand resistance in glioblastoma and thus have an impact on ongoing clinical trials of TNF-related apoptosis-inducing ligand- targeted combination cancer therapies.
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