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Playing the DISC: turning on TRAIL death receptor-mediated apoptosis in cancer.

Authors: Pennarun, B  Meijer, A  De Vries, EG  Kleibeuker, JH  Kruyt, F  De Jong, S 
Citation: Pennarun B, etal., Biochim Biophys Acta. 2010 Apr;1805(2):123-40. Epub 2009 Dec 2.
Pubmed: (View Article at PubMed) PMID:19961901
DOI: Full-text: DOI:10.1016/j.bbcan.2009.11.004

Formation of the pro-apoptotic death-inducing signaling complex (DISC) can be initiated in cancer cells via binding of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to its two pro-apoptotic receptors, TRAIL receptor 1 (TRAIL-R1) and TRAIL-R2. Primary components of the DISC are trimerized TRAIL-R1/-R2, FADD, caspase 8 and caspase 10. The anti-apoptotic protein FLIP can also be recruited to the DISC to replace caspase 8 and form an inactive complex. Caspase 8/10 processing at the DISC triggers the caspase cascade, which eventually leads to apoptotic cell death. Besides TRAIL, TRAIL-R1- or TRAIL-R2-selective variants of TRAIL and agonistic antibodies have been designed. These ligands are of interest as anti-cancer agents since they selectively kill tumor cells. To increase tumor sensitivity to TRAIL death receptor-mediated apoptosis and to overcome drug resistance, TRAIL receptor ligands have already been combined with various therapies in preclinical models. In this review, we discuss factors influencing the initial steps of the TRAIL apoptosis signaling pathway, focusing on mechanisms modulating DISC assembly and caspase activation at the DISC. These insights will direct rational design of drug combinations with TRAIL receptor ligands to maximize DISC signaling.

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RGD Object Information
RGD ID: 4143171
Created: 2010-09-15
Species: All species
Last Modified: 2010-09-15
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.