A20 ubiquitin ligase-mediated polyubiquitination of RIP1 inhibits caspase-8 cleavage and TRAIL-induced apoptosis in glioblastoma

Anita C. Bellail, Jeffrey J. Olson, Xiaolu Yang, Zhijian J. Chen, Chunhai Hao

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)140-155
Number of pages16
JournalCancer Discovery
Volume2
Issue number2
DOIs
StatePublished - Feb 2012

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TNF-Related Apoptosis-Inducing Ligand
Caspase 8
Glioblastoma
Ligases
Ubiquitin
Apoptosis
Death Domain Receptor Signaling Adaptor Proteins
Receptor-Interacting Protein Serine-Threonine Kinases
Cell Membrane
Clinical Trials
Polyubiquitin
TNF-Related Apoptosis-Inducing Ligand Receptors
Neoplasms
Ubiquitin-Protein Ligases
Neoplastic Stem Cells
Ubiquitination
Zinc Fingers
Dimerization
Therapeutics
Lysine

ASJC Scopus subject areas

  • Oncology

Cite this

A20 ubiquitin ligase-mediated polyubiquitination of RIP1 inhibits caspase-8 cleavage and TRAIL-induced apoptosis in glioblastoma. / Bellail, Anita C.; Olson, Jeffrey J.; Yang, Xiaolu; Chen, Zhijian J.; Hao, Chunhai.

In: Cancer Discovery, Vol. 2, No. 2, 02.2012, p. 140-155.

Research output: Contribution to journalArticle

Bellail, Anita C. ; Olson, Jeffrey J. ; Yang, Xiaolu ; Chen, Zhijian J. ; Hao, Chunhai. / A20 ubiquitin ligase-mediated polyubiquitination of RIP1 inhibits caspase-8 cleavage and TRAIL-induced apoptosis in glioblastoma. In: Cancer Discovery. 2012 ; Vol. 2, No. 2. pp. 140-155.
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