Abstract
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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2188-2) contains supplementary material, which is available to authorized users.
Highlights
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
The combination of bicalutamide and vorinostat commits AR-dependent prostate cancer cells to death within 8 h of culture Combining the AR antagonist bicalutamide with the histone deacetylase (HDAC) inhibitor vorinostat induces synergistic cell death of prostate cancer cells, with multiple features characteristic of apoptosis [26]
In order to accurately tailor the design of microarray studies, the timing and cellular requirements for cell death induced by the combination were determined in AR-dependent prostate cancer cells
Summary
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. A number of mechanisms, including increased levels of the AR mRNA or protein [4,5,6,7,8], mutation of the AR gene to produce more active or promiscuous forms of the receptor [9,10,11,12,13,14], altered levels of AR coregulators (reviewed in [15]), the expression of constitutively active AR splice variants [16,17,18], and adrenal and intratumoral biosynthesis of androgens [19,20,21,22,23], explain continued AR signaling during ADT As many of these mechanisms are Carter et al BMC Cancer (2016) 16:141 refractory to conventional ADT, there is considerable impetus to develop new and more potent agents targeting the androgen signaling axis. Phase III clinical trials demonstrated that these agents extend median survival of men with advanced CRPC by several months and both have received FDA approval [25]
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