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.