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J. Biol. Chem., Vol. 279, Issue 42, 44211-44218, October 15, 2004

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

Ying-Yu Wu, Yung-Chi Chang, Tsui-Ling Hsu, Shie-Liang Hsieh, and Ming-Zong Lai¶||

From the Institute of Microbiology and Immunology, National Yang-Ming University, Institute of Molecular Biology, Academia Sinica, and ^¶Institute of Immunology, National Taiwan University, Taipei 11529, Taiwan, Republic of China

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.

Received for publication, August 3, 2004 , and in revised form, August 10, 2004.

^* This work was supported in part by Grant NHRI-EX92-9217BI and a grant from Academia Sinica. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. Tel: 886-2-2789-9236; Fax: 886-2-2782-6085; E-mail: mblai{at}ccvax.sinica.edu.tw.

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