IΚBα mediates prostate cancer cell death induced by combinatorial targeting of the androgen receptor

Sarah L. Carter; Margaret M. Centenera; Wayne D. Tilley; Luke A. Selth; Lisa M. Butler

doi:10.1186/s12885-016-2188-2

IΚBα mediates prostate cancer cell death induced by combinatorial targeting of the androgen receptor

Sarah L. Carter, Margaret M. Centenera, Wayne D. Tilley, Luke A. Selth, Lisa M. Butler

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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-ΚB 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.

Original language	English
Article number	141
Journal	BMC Cancer
Volume	16
DOIs	https://doi.org/10.1186/s12885-016-2188-2
Publication status	Published - 23 Feb 2016
Externally published	Yes

Bibliographical note

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.

Keywords

Androgen receptor
Combination therapy
IΚBα
Prostate cancer

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "IΚBα mediates prostate cancer cell death induced by combinatorial targeting of the androgen receptor",

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-ΚB 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 = "Androgen receptor, Combination therapy, IΚBα, Prostate cancer",

author = "Carter, {Sarah L.} and Centenera, {Margaret M.} and Tilley, {Wayne D.} and Selth, {Luke A.} and Butler, {Lisa M.}",

note = "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.",

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AU - Carter, Sarah L.

AU - Centenera, Margaret M.

AU - Tilley, Wayne D.

AU - Selth, Luke A.

AU - Butler, Lisa M.

N1 - 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.

PY - 2016/2/23

Y1 - 2016/2/23

N2 - 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-ΚB 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.

AB - 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-ΚB 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.

KW - Androgen receptor

KW - Combination therapy

KW - IΚBα

KW - Prostate cancer

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M1 - 141

ER -

IΚBα mediates prostate cancer cell death induced by combinatorial targeting of the androgen receptor

Abstract

Bibliographical note

Keywords

UN SDGs

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