Sensitization of cells to TRAIL-induced apoptosis by decoy receptor 3.
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 beta 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.
Wu
Ying-Yu
YY
Institute of Microbiology and Immunology, National Yang-Ming University, Taiwan, Republic of China.
Chang
Yung-Chi
YC
Hsu
Tsui-Ling
TL
Hsieh
Shie-Liang
SL
Lai
Ming-Zong
MZ
D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D016923:Cell Death; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor; D053323:Receptors, Tumor Necrosis Factor, Member 6b; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D020298:U937 Cells; D019014:fas Receptor / Q000032:analysis
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D053323:Receptors, Tumor Necrosis Factor, Member 6b; D053221:TNF-Related Apoptosis-Inducing Ligand; C505911:TNFRSF6B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor