A Smac-mimetic sensitizes prostrate cancer cells to TRAIL-induced apoptosis via modulating IAPs and NF-kappaB

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Issue Date
2009-11-06Author
Dai, Yao
Liu, Meilan
Tang, Wenhua
Li, Yongming
Lian, Jiqin
Lawrence, Theodore S.
Xu, Liang
Publisher
BioMed Central
Type
Article
Article Version
Scholarly/refereed, publisher version
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.
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Show full item recordAbstract
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.
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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
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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.