PT  - JOURNAL ARTICLE
AU  - Kim, Hun Sik
AU  - Chang, Inik
AU  - Kim, Ja Young
AU  - Choi, Kyung-Hee
AU  - Lee, Myung-Shik
TI  - Caspase-Mediated p65 Cleavage Promotes TRAIL-Induced Apoptosis
AID  - 10.1158/0008-5472.CAN-05-0472
DP  - 2005 Jul 15
TA  - Cancer Research
PG  - 6111--6119
VI  - 65
IP  - 14
4099  - http://cancerres.aacrjournals.org/content/65/14/6111.short
4100  - http://cancerres.aacrjournals.org/content/65/14/6111.full
SO  - Cancer Res2005 Jul 15; 65
AB  - 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 κB (NF-κB) activation and overcomes its antiapoptotic effect. We explored the regulation of NF-κB activity by TRAIL and its role in apoptosis. TRAIL combined with IκBα-“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 IκBα-superrepressor. Although TRAIL alone did not induce NF-κB activity, TRAIL combined with z-VAD significantly increased NF-κB activation. Analysis of the NF-κB 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-κB activity in TRAIL-treated cells. Cleavage-resistant p65D97A further increased NF-κB 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-κB activation, but simultaneously abrogates NF-κB 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. ©2005 American Association for Cancer Research.