Sensitization of Cells to TRAIL-induced Apoptosis by Decoy Receptor 3

Abstract

Decoy receptor 3 (DcR3)/TR6/M68 is a soluble receptor that binds to the Fas ligand LIGHT and TL1A. Elevated levels of DcR3 expression have been found in many tumors. We report an unexpected effect of DcR3 by sensitizing Jurkat and U937 cells to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Cell death triggered by anti-Fas and tumor necrosis factor was unaffected by DcR3. DcR3 by itself did not stimulate apoptosis. The ability to augment TRAIL-initiated cell death was not observed with soluble lymphotoxin ␤ receptor or soluble death receptor 3, indicating that binding to LIGHT or TL1A alone is insufficient to trigger TRAIL sensitivity. Incubation with DcR3 did not increase the surface expression of TRAIL receptor, and the level of Fas-associated death domain protein and cellular FLICE-like inhibitory protein was not altered. Instead, in the presence of DcR3, TRAIL engagement resulted in an increased activation of caspase-8, an elevated cleavage of Bid, and enhanced release of Smac and cytochrome c from mitochondria to cytosol compared with TRAIL alone. This led to increased activation of caspase-9 and caspase-3. The unusual ability of DcR3 to promote TRAIL-triggered death may be used to potentiate TRAIL efficacy during treatment tumors overexpressing DcR3. Decoy receptor 3 (DcR3)1 /TR6/M68 is a member of the tumor necrosis factor receptor superfamily (1). DcR3 binds to at least three different ligands: Fas ligand (FasL), LIGHT, and TL1A (1-3). The biological functions initiated by these three ligands are blocked by the presence of DcR3. DcR3 is overexpressed in primary lung and colon tumors (1), in gliomas (4), gastrointestinal tract tumors (5, 6), autoimmune tissues (7), and virusassociated leukemia (8). It has been suggested that DcR3 acts as a decoy receptor for tumor cells to neutralize the cytotoxic and regulatory effects of FasL, LIGHT, and TL1A, in that inoculation of rats with glioma cells overexpressing DcR3 resulted in decreased infiltration of T cells and macrophages (4).DcR3 has also been shown to promote angiogenesis through neutralization of TL1A (9).Recent studies have revealed the profound modulatory effects of DcR3 on many cells. DcR3 regulates CD14 ϩ monocyte differentiation into dendritic cells, with down-regulation of HLA-DR, CD56/ICAM-1, and CD80, and up-regulation of CD86 in mature dendritic cells, leading to skewed Th2 differentiation in primed T cells (10). DcR3 attenuates T cell activation and reduces T cell response to mouse heart allograft (11). DcR3 also decreases T cell interaction with antigen-presenting cells (12) and inhibits T cell chemotaxis (13). In addition, DcR3 triggers actin re-organization, increases the adhesion of monocytes (14), and reduces phagocytic activity and proinflammatory cytokine production in macrophages (15).TRAIL induces apoptosis by binding to TRAIL receptor (16, 17). There are five different TRAIL receptors, including TRAIL-R1/DR4, TRAIL-R2/DR5, TRAIL-R3/DcR1, TRAIL-R4/ DcR2, and osteoprotegerin. Binding of DR4 and DR...

Morusin Induces TRAIL Sensitization by Regulating EGFR and DR5 in Human Glioblastoma Cells

“…Even though TRAIL is considered an important therapeutic agent for tumor treatment, clinical trials have revealed its limitations due to the acquisition of tumor resistance. There are lots of mechanisms by which tumor cells acquire TRAIL resistance, such as induction of decoy receptors (DcR1 and DcR2), 29,33 anti-apoptotic proteins (c-FLIP, IAPs, Bcl2, Bcl-xL, and Mcl-1), 34−36 and proliferation activators (PI3K, AKT, and NF-κB). 37−39 Another major strategy to induce TRAIL resistance is to suppress death receptors DR5 and/or DR4.…”

Overexpression of Par‐4 sensitizes TRAIL‐induced apoptosis via inactivation of NF‐κB and Akt signaling pathways in renal cancer cells

“…It has been reported that several genes increased the sensitivity to TRAIL via activating pro‐apoptotic factors or suppressing anti‐apoptotic factors. For example, (i) adenoviral vector expressing CYLD increased the sensitivity to TRAIL by suppression of NF‐κB survival signaling in hepatocellular carcinoma [Chu et al, 2006]; (ii) somatostatin receptor subtype 2 (sst2) up‐regulated expression of DR4 and TNFRI, sensitizing the cells to death ligand‐induced initiator capase‐8 activation, as well as down‐regulated expression of the antiapoptotic mitochondrial Bcl‐2 protein [Guillermet et al, 2003]; (iii) decoy receptor 3 (DcR3) increased TRAIL‐induced caspase‐8 activation and Bid cleavage, enhanced Smac release from mitochondria, and augmented caspases‐3 and ‐9 activation [Wu et al, 2004]; (iv) overexpression of reticulon 3 (RTN3) enhances TRAIL‐mediated apoptosis via up‐regulation of death receptor 5 (DR5) and down‐regulation of c‐FLIP [Lee et al, 2009]; (v) prostate apoptosis response gene‐4 (par‐4) enhances sensitivity towards TRAIL by an enforced cleavage of c‐FLIP L together with an increased activation of the initiator caspases‐8 and ‐10 and expression of par‐4 enables cells to down‐regulate the inhibitor‐of‐apoptosis proteins c‐IAP‐1, c‐IAP‐2, XIAP, and survivin [Boehrer et al, 2006]. However, Boehrer et al reported that Par‐4 promotes apoptosis induced by TRAIL through activation of caspase‐dependent pathway, its sensitizing mechanism was not determined.…”

Decoy Receptor 3 Suppresses T-Cell Priming and Promotes Apoptosis of Effector T-Cells in Acute Cell-Mediated Rejection: The Role of Reverse Signaling

“…DcR3 enhances apoptosis in TRAIL-sensitive transformed T-cells without triggering any apoptotic event ( 28 ). TRAIL and FasL, which play major roles in allograft rejection ( 13 , 29 ), were detected in T-cells co-cultured with BMDCs using western blot ( Supplementary Figure S7 ).…”