%0 Journal Article
%T A Smac-mimetic sensitizes prostate cancer cells to TRAIL-induced apoptosis via modulating both IAPs and NF-kappaB
%A Yao Dai
%A Meilan Liu
%A Wenhua Tang
%A Yongming Li
%A Jiqin Lian
%A Theodore S Lawrence
%A Liang Xu
%J BMC Cancer
%D 2009
%I BioMed Central
%R 10.1186/1471-2407-9-392
%X The potential of Smac-mimetics to bind XIAP or cIAP-1 was examined by pull-down assay. Cytotoxicity of TRAIL and/or Smac-mimetics was determined by a standard cell growth assay. Silencing of XIAP or cIAP-1 was achieved by transient transfection of short hairpin RNA. Apoptosis was detected by Annexin V-PI staining followed by flow cytometry and by Western Blot analysis of caspases, PARP and Bid. NF-kappaB activation was determined by subcellular fractionation, real time RT-PCR and reporter assay.SH122, but not its inactive analog, binds to XIAP and cIAP-1. SH122 significantly sensitized prostate cancer cells to TRAIL-mediated cell death. Moreover, SH122 enhanced TRAIL-induced apoptosis via both the death receptor and the mitochondrial pathway. Knockdown of both XIAP and cIAP-1 sensitized cellular response to TRAIL. XIAP-knockdown attenuated sensitivity of SH122 to TRAIL-induced cytotoxicity, confirming that XIAP is an important target for IAP-inhibitor-mediated TRAIL sensitization. SH122 also suppressed TRAIL-induced NF-kappaB activation by preventing cytosolic IkappaB-alpha degradation and RelA nuclear translocation, as well as by suppressing NF-kappaB target gene expression.These results demonstrate that SH122 sensitizes human prostate cancer cells to TRAIL-induced apoptosis by mimicking Smac and blocking both IAPs and NF-kappaB. Modulating IAPs may represent a promising approach to overcoming TRAIL-resistance in human prostate cancer with constitutively active NF-kappaB signaling.Primary or acquired resistance of prostate cancer to current treatment protocols has been associated with apoptosis-resistance in cancer cells, leading to therapy failure [1,2]. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family that is in clinical trials for the treatment of prostate cancer, either alone or in combination with other treatments [3]. TRAIL selectively induces apoptosis in prostate cancer cells compared to normal prostate epithelia
%U http://www.biomedcentral.com/1471-2407/9/392