Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/100168
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Type: Journal article
Title: IκBα mediates prostate cancer cell death induced by combinatorial targeting of the androgen receptor
Other Titles: IkappaBalpha mediates prostate cancer cell death induced by combinatorial targeting of the androgen receptor
Author: Carter, S.
Centenera, M.
Tilley, W.
Selth, L.
Butler, L.
Citation: BMC Cancer, 2016; 16(1):141-1-141-13
Publisher: BioMed Central
Issue Date: 2016
ISSN: 1471-2407
1471-2407
Statement of
Responsibility: 
Sarah L. Carter, Margaret M. Centenera, Wayne D. Tilley, Luke A. Selth, and Lisa M. Butler
Abstract: Background: Combining different clinical agents to target multiple pathways in prostate cancer cells, including androgen receptor (AR) signaling, is potentially an effective strategy to improve outcomes for men with metastatic disease. We have previously demonstrated that sub-effective concentrations of an AR antagonist, bicalutamide, and the histone deacetylase inhibitor, vorinostat, act synergistically when combined to cause death of AR-dependent prostate cancer cells. Methods: In this study, expression profiling of human prostate cancer cells treated with bicalutamide or vorinostat, alone or in combination, was employed to determine the molecular mechanisms underlying this synergistic action. Cell viability assays and quantitative real time PCR were used to validate identified candidate genes. Results: A substantial proportion of the genes modulated by the combination of bicalutamide and vorinostat were androgen regulated. Independent pathway analysis identified further pathways and genes, most notably NFKBIA (encoding IκBα , an inhibitor of NF- κ B and p53 signaling), as targets of this combinatorial treatment. Depletion of IκBα by siRNA knockdown enhanced apoptosis of prostate cancer cells, while ectopic overexpression of IκBα markedly suppressed cell death induced by the combination of bicalutamide and vorinostat. Conclusion: These findings implicate IκBα as a key mediator of the apoptotic action of this combinatorial AR targeting strategy and a promising new therapeutic target for prostate cancer.
Keywords: Prostate cancer; androgen receptorl; combination therapy; IκBα
Rights: © 2016 Carter et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
RMID: 0030046547
DOI: 10.1186/s12885-016-2188-2
Grant ID: http://purl.org/au-research/grants/nhmrc/627185
http://purl.org/au-research/grants/arc/FT130101004
Appears in Collections:Medicine publications

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