title: NFκB signalling is upregulated in a subset of castrate-resistant prostate cancer patients and correlates with disease progression.
abstract: BACKGROUND
  Cell line models suggest that activation of NFκB is associated with progression of prostate cancer. This pathway may be a therapeutic target if these observations translate to clinical specimens.
  
  
  METHODS
  Immunohistochemistry measured NFκBp65 (p65), NFκBp65 nuclear localisation signal (NLS), NFκBp65 phosphorylated at ser 276 (p65(ser276)), NFκBp65 phosphorylated at ser 536 (p65(ser536)), IκBα phosphorylated at ser 32/36 (pIκBα(ser32/36)) and MMP-9 protein expression in 61 matched hormone naive prostate cancer (HNPC) and castrate-resistant prostate cancer (CRPC) tumours. Animal and cell models were used to investigate the role of NFκB inhibition in prostate carcinogenesis.
  
  
  RESULTS
  In HNPC tumours, NLS expression significantly associated with a shorter time to disease recurrence and disease-specific death. In CRPC tumours p65, pIκBα(ser32/36) and MMP-9 expression significantly associated with shorter time to death from disease recurrence and shorter disease-specific death. MMP-9 and pIκBα(ser32/36) expression significantly associated with metastases at recurrence and were independent of Gleason sum and prostate-specific antigen at recurrence. Expression of phosphorylated Akt was associated with increased p65 activation in mouse models and inhibition of NFκB in LNCaP cells significantly reduced cellular proliferation and induced apoptosis.
  
  
  CONCLUSIONS
  These results provide further evidence that the NFκB pathway could be exploited as a target for CRPC.
authors.affiliation: Unit of Experimental therapeutics, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ UK. pamela.mccall@glasgow.ac.uk
authors.forename: P
authors.initials: P
authors.lastname: McCall
authors.forename: L
authors.initials: L
authors.lastname: Bennett
authors.forename: I
authors.initials: I
authors.lastname: Ahmad
authors.forename: L M
authors.initials: LM
authors.lastname: Mackenzie
authors.forename: I W G
authors.initials: IW
authors.lastname: Forbes
authors.forename: H Y
authors.initials: HY
authors.lastname: Leung
authors.forename: O J
authors.initials: OJ
authors.lastname: Sansom
authors.forename: C
authors.initials: C
authors.lastname: Orange
authors.forename: M
authors.initials: M
authors.lastname: Seywright
authors.forename: M A
authors.initials: MA
authors.lastname: Underwood
authors.forename: J
authors.initials: J
authors.lastname: Edwards
mesh_terms: D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D015331:Cohort Studies; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D020780:Matrix Metalloproteinase 9