A Smac-mimetic sensitizes prostrate cancer cells to TRAIL-induced apoptosis via modulating IAPs and NF-kappaB
dc.contributor.author | Dai, Yao | |
dc.contributor.author | Liu, Meilan | |
dc.contributor.author | Tang, Wenhua | |
dc.contributor.author | Li, Yongming | |
dc.contributor.author | Lian, Jiqin | |
dc.contributor.author | Lawrence, Theodore S. | |
dc.contributor.author | Xu, Liang | |
dc.date.accessioned | 2014-08-13T18:00:34Z | |
dc.date.available | 2014-08-13T18:00:34Z | |
dc.date.issued | 2009-11-06 | |
dc.identifier.citation | Dai,Y., Liu, M., Tang, W., Li, Y., Lian, J., Lawrence, T.S., Xu, L. A Smac-mimetic sensitizes prostrate cancer cells to TRAIL-induced apoptosis via modulating both IAPs and NF-kappaB. BMC Cancer 2009, 9:392. http://dx.doi.org/10.1186/1471-2407-9-392 | |
dc.identifier.uri | http://hdl.handle.net/1808/14919 | |
dc.description.abstract | Background: Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for human cancer therapy, prostate cancer still remains resistant to TRAIL. Both X-linked inhibitor of apoptosis (XIAP) and nuclear factor-kappaB function as key negative regulators of TRAIL signaling. In this study, we evaluated the effect of SH122, a small molecule mimetic of the second mitochondria-derived activator of caspases (Smac), on TRAIL-induced apoptosis in prostate cancer cells. Methods: 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. Results: 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-inhibitormediated 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. Conclusion: 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. | |
dc.language.iso | en | |
dc.publisher | BioMed Central | |
dc.rights | This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. | |
dc.rights.uri | http://creativecommons.org/licenses/by/2.0 | |
dc.title | A Smac-mimetic sensitizes prostrate cancer cells to TRAIL-induced apoptosis via modulating IAPs and NF-kappaB | |
dc.type | Article | |
kusw.kuauthor | Xu, Liang | |
kusw.kudepartment | Molecular Biosciences | |
kusw.oastatus | na | |
dc.identifier.doi | 10.1186/1471-2407-9-392 | |
kusw.oaversion | Scholarly/refereed, publisher version | |
kusw.oapolicy | This item does not meet KU Open Access policy criteria. | |
dc.rights.accessrights | openAccess |
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Except where otherwise noted, this item's license is described as: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.