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

BMC Cancer

Research Article

Sarah L. Carter¹  Wayne D. Tilley¹  Luke A. Selth¹  Lisa M. Butler²  Margaret M. Centenera² 

[1] Dame Roma Mitchell Cancer Research Laboratories, Adelaide Prostate Cancer Research Centre and Freemason’s Foundation Centre for Men’s Health, School of Medicine, University of Adelaide and Hanson Institute, 5005, Adelaide, SA, Australia;Dame Roma Mitchell Cancer Research Laboratories, Adelaide Prostate Cancer Research Centre and Freemason’s Foundation Centre for Men’s Health, School of Medicine, University of Adelaide and Hanson Institute, 5005, Adelaide, SA, Australia;Cancer Theme, South Australian Health and Medical Research Institute, 5001, Adelaide, SA, Australia;

关键词: Prostate cancer;    Androgen receptor;    Combination therapy;    IκBα;   

DOI  :  10.1186/s12885-016-2188-2

 received in 2015-07-06, accepted in 2016-02-16,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundCombining 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.MethodsIn 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.ResultsA 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.ConclusionThese 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.

【 授权许可】

CC BY   
© Carter et al. 2016