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.

Coinhibition of the deubiquitinating enzymes, USP14 and UCHL5, with VLX1570 is lethal to ibrutinib- or bortezomib-resistant Waldenstrom macroglobulinemia tumor cells

“…18 The role of USP14 and UCHL5 in maintaining cancer cell viability and providing growth advantage is increasingly being recognized in a variety of cancers, including hematologic malignancies. 30 Although the precise molecular contributions made by these two DUBs towards tumor cell survival continue to be studied, 34, 46, 47, 48, 49, 50 efforts to target their dysregulated (and often increased) activity are underway, notably in MM and WM. 23, 30 Herein, we extend our initial observations that USP14 and UCHL5 are highly expressed in drug-resistant WM tumor cells including those from WM patients as compared with PBMCs or resident bone marrow cells from healthy donors.…”

Inhibition of 19S proteasome-associated deubiquitinases by metal-containing compounds

“…b-AP15 triggers apoptosis in the multiple myeloma (MM) cells and patient MM cells through caspase activation and overcomes 20S proteasome inhibitor bortezomib resistance [88-89]. 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 [90]. b-AP15-induced sensitization to TRAIL-mediated apoptosis could be used as a novel strategy to augment the anticancer effects of adoptively infused NK and T cells in patients with cancer [91].…”

Inhibition of IRE1 modifies effect of glucose deprivation on the expression of TNF?-related genes in U87 glioma cells

“…In this case we also have opposite effects of glucose deprivation and IRE1 inhibition. There is data that TNFRSF10D lacking the pro-apoptotic death domain, cannot induce apoptosis and has been shown to play an inhibitory role in TRAIL-induced cell apoptosis [21,24]. The induction of TNFRSF10D mRNA in glioma cells upon inhibition of IRE1 correlates with down-regulation of TNFRSF10B/DR5.…”

“…Conversely the decoy receptors TRAILR3 and TRAILR4, which lack the pro-apoptotic death domain, function to dampen the apoptotic response by competing for TRAIL ligand. TRAILR4 does not induce apoptosis, and has been shown to play an inhibitory role in TRAIL-induced cell apoptosis [20,21,24].…”