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Int. J. Mol. Sci. 2014, 15(10), 18557-18573; doi:10.3390/ijms151018557

Regulation of TRAIL-Receptor Expression by the Ubiquitin-Proteasome System

Karolinska Institutet, Department of Oncology-Pathology, Stockholm S-17176, Sweden
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Received: 27 August 2014 / Revised: 30 September 2014 / Accepted: 2 October 2014 / Published: 14 October 2014
(This article belongs to the Collection Programmed Cell Death and Apoptosis)
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Abstract

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand- receptor (TRAIL-R) family has emerged as a key mediator of cell fate and survival. Ligation of TRAIL ligand to TRAIL-R1 or TRAIL-R2 initiates the extrinsic apoptotic pathway characterized by the recruitment of death domains, assembly of the death-inducing signaling complex (DISC), caspase activation and ultimately apoptosis. Conversely the decoy receptors TRAIL-R3 and TRAIL-R4, which lack the pro-apoptotic death domain, function to dampen the apoptotic response by competing for TRAIL ligand. The tissue restricted expression of the decoy receptors on normal but not cancer cells provides a therapeutic rational for the development of selective TRAIL-mediated anti-tumor therapies. Recent clinical trials using agonistic antibodies against the apoptosis-inducing TRAIL receptors or recombinant TRAIL have been promising; however the number of patients in complete remission remains stubbornly low. The mechanisms of TRAIL resistance are relatively unexplored but may in part be due to TRAIL-R down-regulation or shedding of TRAIL-R by tumor cells. Therefore a better understanding of the mechanisms underlying TRAIL resistance is required. The ubiquitin-proteasome system (UPS) has been shown to regulate TRAIL-R members suggesting that pharmacological inhibition of the UPS may be a novel strategy to augment TRAIL-based therapies and increase efficacies. We recently identified b-AP15 as an inhibitor of proteasome deubiquitinase (DUB) activity. Interestingly, exposure of tumor cell lines to b-AP15 resulted in increased TRAIL-R2 expression and enhanced sensitivity to TRAIL-mediated apoptosis and cell death in vitro and in vivo. In conclusion, targeting the UPS may represent a novel strategy to increase the cell surface expression of pro-apoptotic TRAIL-R on cancer cells and should be considered in clinical trials targeting TRAIL-receptors in cancer patients. View Full-Text
Keywords: TNF-related apoptosis-inducing ligand (TRAIL); apoptosis; cancer; ubiquitin-proteasome system (UPS); natural killer (NK) cells; T cells TNF-related apoptosis-inducing ligand (TRAIL); apoptosis; cancer; ubiquitin-proteasome system (UPS); natural killer (NK) cells; T cells
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Sarhan, D.; D'Arcy, P.; Lundqvist, A. Regulation of TRAIL-Receptor Expression by the Ubiquitin-Proteasome System. Int. J. Mol. Sci. 2014, 15, 18557-18573.

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