Wu Ying-Yu, Chang Yung-Chi, Hsu Tsui-Ling, Hsieh Shie-Liang, Lai Ming-Zong
Institute of Microbiology and Immunology, National Yang-Ming University, Taiwan, Republic of China.
J Biol Chem. 2004 Oct 15;279(42):44211-8. doi: 10.1074/jbc.408842200.
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.
诱饵受体3（DcR3）/TR6/M68是一种可溶受体，能与Fas配体、LIGHT和TL1A结合。在许多肿瘤中都发现DcR3表达水平升高。我们报告了DcR3的一个意外作用，即它能使Jurkat细胞和U937细胞对肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的凋亡敏感。抗Fas和肿瘤坏死因子引发的细胞死亡不受DcR3影响。DcR3自身不会刺激细胞凋亡。可溶性淋巴毒素β受体或可溶性死亡受体3未观察到增强TRAIL引发细胞死亡的能力，这表明单独与LIGHT或TL1A结合不足以触发TRAIL敏感性。与DcR3孵育不会增加TRAIL受体的表面表达，Fas相关死亡结构域蛋白和细胞FLICE样抑制蛋白的水平也未改变。相反，与单独的TRAIL相比，在存在DcR3的情况下，TRAIL结合导致半胱天冬酶-8的激活增加、Bid的切割增强以及Smac和细胞色素c从线粒体向细胞质的释放增强。这导致半胱天冬酶-9和半胱天冬酶-3的激活增加。DcR3促进TRAIL引发死亡的这种异常能力可用于在治疗过表达DcR3的肿瘤期间增强TRAIL的疗效。
