A20 Ubiquitin Ligase-Mediated Polyubiquitination of RIP1 Inhibits Caspase-8 Cleavage and TRAIL-Induced Apoptosis in Glioblastoma (Cancer Discovery 2012;2:140-155)

報告日期: 2014/04/25
報告時間: 4:00/4:50
報告學生: 陳智源
講評老師: 洪建中
附件下載: 下載[1400-1396958520-1.pdf] 

A20 Ubiquitin Ligase-Mediated Polyubiquitination of RIP1 Inhibits Caspase-8 Cleavage and TRAIL-Induced Apoptosis in Glioblastoma

 

Anita C Bellail et al.

Cancer Discovery 2012;2:140-155.

Speaker: Zhi-Yuan Chen                    Date: 2014/04/25 16:00-16:50

Commentator: Jan-Jong, Hung Ph.D.           Room: 602

 

Abstract

The TNF-related apoptosis-inducing ligand (TRAIL) induced extrinsic apoptotic pathway has been as a treatment of cancer target. However, clinical trials observed cancers are resistant to TRAIL induced apoptosis and maybe associated with ubiquitination. In this study, they find A20 that contains ubiquitination and deubiquitination dual roles is highly expressed in glioblastomas. It can bind with death receptor 5 and receptor-interacting protein 1 (RIP1), forms a preligand assembly complex (PLAC) in plasma membrane when the TRAIL-resistance occurs. TRAIL-resistance leads to recruitment of caspase-8 to the plasma membrane, assembly with PLAC for a death-inducing signaling complex (DISC). In DISC, the A20 C-terminal zinc finger (Znf) domain of an ubiquitin ligase mediates RIP1 polyubiquitination through lysine-63-linked polyubiquitin chains. Moreover, this polyubiquitin chain binding to the caspase-8 protease domain to inhibit caspase-8 dimerization and cleavage in glioblastoma-derived cell lines and tumor-initiating cells. These results suggest that inhibition of RIP1 polyubiquitination maybe a potential target in future therapy to avoid TRAIL-resistance.

 

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