ATTENTION: The software behind KU ScholarWorks is being upgraded to a new version. Starting July 15th, users will not be able to log in to the system, add items, nor make any changes until the new version is in place at the end of July. Searching for articles and opening files will continue to work while the system is being updated.
If you have any questions, please contact Marianne Reed at mreed@ku.edu .
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 |
Files in this item
This item appears in the following Collection(s)
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.