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Caspase-Mediated p65 Cleavage Promotes TRAIL-Induced Apoptosis

¹ Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine and ² Department of Biology, College of Natural Sciences, Chung-Ang University, Seoul, Korea

Requests for reprints: Myung-Shik Lee, Department of Medicine, Samsung Medical Center, 50 Irwon-dong Kangnam-ku, Seoul 135-710, Korea. Phone: 82-2-3410-3436; Fax: 82-2-3410-0388; E-mail: mslee{at}smc.samsung.co.kr.

Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) is cytotoxic to a wide variety of transformed cells, but not to most normal cells, implying potential therapeutic value against advanced cancer. However, signal transduction in TRAIL-mediated apoptosis is not clearly understood compared with other TNF family members. Specifically, it is not yet understood how TRAIL controls nuclear factor B (NF-B) activation and overcomes its antiapoptotic effect. We explored the regulation of NF-B activity by TRAIL and its role in apoptosis. TRAIL combined with IB-"superrepressor" induced potent apoptosis of SK-Hep1 hepatoma cells at low concentrations of TRAIL that do not independently induce apoptosis. Apoptosis by high concentrations of TRAIL was not affected by IB-superrepressor. Although TRAIL alone did not induce NF-B activity, TRAIL combined with z-VAD significantly increased NF-B activation. Analysis of the NF-B activation pathway indicated that TRAIL unexpectedly induced cleavage of p65 at Asp⁹⁷, which was blocked by z-VAD, accounting for all of these findings. p65 expression abrogated apoptosis and increased NF-B activity in TRAIL-treated cells. Cleavage-resistant p65^D97A further increased NF-B activity in TRAIL-treated cells, whereas the COOH-terminal p65 fragment acted as a dominant-negative inhibitor. XIAP levels were increased by TRAIL in combination with z-VAD, whereas XIAP levels were decreased by TRAIL alone. Cleavage of p65 was also detected after FRO thyroid cancer cells were treated with TRAIL. These results suggest that TRAIL induces NF-B activation, but simultaneously abrogates NF-B activation by cleaving p65, and thereby inhibits the induction of antiapoptotic proteins such as XIAP, which contributes to the strong apoptotic activity of TRAIL compared with other TNF family members.

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