NFκB signalling is upregulated in a subset of castrate-resistant prostate cancer patients and correlates with disease progression

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. CONCLUSION: These results provide further evidence that the NFκB pathway could be exploited as a target for CRPC.