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Author Notes:

Correspondence to: Chunhai HAO, Department of Pathology and Laboratory Medicine, Room 5082, Emory University, 1365-C Clifton Road, Atlanta, GA 30322, USA. Tel.: 404-778-4776 Fax: 404-778-5550 E-mail: chao@emory.edu

Subjects:

Research Funding:

This work was supported, in part, by grants from the National Institutes of Health/National Cancer Institute (CA129687) and the Southeastern Brain Tumor Foundation.

Chunhai Hao is the Georgia Cancer Coalition Distinguished Scholar.

Keywords:

  • glioblastoma
  • apoptosis
  • caspase-8
  • DR5
  • TRAIL

DR5-mediated DISC controls caspase-8 cleavage and initiation of apoptosis in human glioblastomas

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Journal Title:

Journal of Cellular and Molecular Medicine

Volume:

Volume 14, Number 6A

Publisher:

, Pages 1303-1317

Type of Work:

Article | Final Publisher PDF

Abstract:

To explore the molecular mechanisms by which glioblastomas are resistant to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), we examined TRAIL signalling pathways in the tumours. TRAIL has four membrane-anchored receptors, death receptor 4/5 (DR4/5) and decoy receptor 1/2 (DcR1/2). Of these receptors, only DR5 was expressed consistently in glioblastoma cell lines and tumour tissues, ruling out the role of DcR1/2 in TRAIL resistance. Upon TRAIL binding, DR5 was homotrimerized and recruited Fas-associated death domain (FADD) and caspase-8 for the assembly of death-inducing signalling complex (DISC) in the lipid rafts of the plasma membrane. In the DISC, caspase-8 was cleaved and initiated apoptosis by cleaving downstream caspases in TRAIL-sensitive glioblastoma cells. In TRAIL-resistant cells, however, DR5-mediated DISC was modified by receptor-interacting protein (RIP), cellular FADD-like interleukin-1β-converting enzyme inhibitory protein (c-FLIP) and phosphoprotein enriched in diabetes or in astrocyte-15 (PED/PEA-15). This DISC modification occurred in the non-raft fractions of the plasma membrane and resulted in the inhibition of caspase-8 cleavage and activation of nuclear factor-κB (NF-κB). Treatment of resistant cells with parthenolide, an inhibitor of inhibitor of κB (I-κB), eliminated TRAIL-induced NF-κB activity but not TRAIL resistance. In contrast, however, targeting of RIP, c-FLIP or PED/PEA-15 with small interfering RNA (siRNA) led to the redistribution of the DISC from non-rafts to lipid rafts and eliminated the inhibition of caspase-8 cleavage and thereby TRAIL resistance. Taken together, this study indicates that the DISC modification by RIP, c-FLIP and PED/PEA-15 is the most upstream event in TRAIL resistance in glioblastomas.

Copyright information:

© 2009 The Authors Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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