Regulation of TRAIL-Receptor Expression by the Ubiquitin-Proteasome System
AbstractThe 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
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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.
Sarhan D, D'Arcy P, Lundqvist A. Regulation of TRAIL-Receptor Expression by the Ubiquitin-Proteasome System. International Journal of Molecular Sciences. 2014; 15(10):18557-18573.Chicago/Turabian Style
Sarhan, Dhifaf; D'Arcy, Padraig; Lundqvist, Andreas. 2014. "Regulation of TRAIL-Receptor Expression by the Ubiquitin-Proteasome System." Int. J. Mol. Sci. 15, no. 10: 18557-18573.