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.