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.
  
  
  CONCLUSIONS
  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.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Carter
authors.affiliation: 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, Adelaide, SA, 5005, Australia. sarahlou.carter@gmail.com.
authors.forename: Sarah Louise
authors.initials: SL
authors.lastname: Carter
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Centenera
authors.affiliation: 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, Adelaide, SA, 5005, Australia. margaret.centenera@adelaide.edu.au.|Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, SA, 5001, Australia. margaret.centenera@adelaide.edu.au.
authors.forename: Margaret Mary
authors.initials: MM
authors.lastname: Centenera
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Tilley
authors.affiliation: 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, Adelaide, SA, 5005, Australia. wayne.tilley@adelaide.edu.au.
authors.forename: Wayne Desmond
authors.initials: WD
authors.lastname: Tilley
authors.forename: Luke A
authors.initials: LA
authors.lastname: Selth
authors.affiliation: 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, Adelaide, SA, 5005, Australia. luke.selth@adelaide.edu.au.
authors.forename: Luke Ashton
authors.initials: LA
authors.lastname: Selth
authors.affiliation: 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, Adelaide, SA, 5005, Australia. lisa.butler@adelaide.edu.au.|Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, SA, 5001, Australia. lisa.butler@adelaide.edu.au.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Butler
authors.forename: Lisa Maree
authors.initials: LM
authors.lastname: Butler
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020672:I-kappa B Proteins / Q000235:genetics*; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D009570:Nitriles / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D014105:Tosyl Compounds / Q000494:pharmacology*; D000077337:Vorinostat
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D009570:Nitriles; D014105:Tosyl Compounds; D000072000:NF-KappaB Inhibitor alpha; D000077337:Vorinostat; C053541:bicalutamide