Regulation of TRAIL-receptor expression by the ubiquitin-proteasome system.

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.

• Authors: Dhifaf Sarhan, Padraig D'Arcy, Andreas Lundqvist
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 15 Issue 10 Pg. 18557-73 (Oct 14 2014) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 25318057 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Tumor Necrosis Factor-alpha
• Ubiquitin
• Proteasome Endopeptidase Complex

Topics

• Animals
• Apoptosis (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Molecular Targeted Therapy
• Neoplasms (drug therapy, genetics, metabolism)
• Proteasome Endopeptidase Complex (metabolism)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (genetics, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)
• Ubiquitin (metabolism)