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A Smac-mimetic sensitizes prostrate cancer cells to TRAIL-induced apoptosis via modulating IAPs and NF-kappaB
Dai, Yao Liu, Meilan Tang, Wenhua Li, Yongming Lian, Jiqin Lawrence, Theodore S. Xu, Liang
Dai, Yao
Liu, Meilan
Tang, Wenhua
Li, Yongming
Lian, Jiqin
Lawrence, Theodore S.
Xu, Liang
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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.
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2009-11-06
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BioMed Central
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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