Nuclear cytokine-activated IKKα controls prostate cancer metastasis by repressing Maspin

Inflammation enhances tumour promotion through NF-kappa B-dependent mechanisms(1). NF-kappa B was also proposed to promote metastatogenesis through epithelial - mesenchymal transition(2). Yet a mechanistic link between inflammation and metastasis is missing. We identified a role for I kappa B kinase alpha (IKK alpha), activated by receptor activator of NF-kappa B (RANK/TNFRSF11A), in mammary epithelial proliferation during pregnancy(3). Owing to similarities between mammary and prostate epithelia, we examined IKK alpha involvement in prostate cancer and its progression. Here we show that a mutation that prevents IKK alpha activation slows down CaP growth and inhibits metastatogenesis in TRAMP mice, which express SV40 T antigen in the prostate epithelium(4). Decreased metastasis correlated with elevated expression of the metastasis suppressor Maspin(5), the ablation of which restored metastatic activity. IKK alpha activation by RANK ligand (RANKL/TNFSF11) inhibits Maspin expression in prostate epithelial cells, whereas repression of Maspin transcription requires nuclear translocation of active IKK alpha. The amount of active nuclear IKK alpha in mouse and human prostate cancer correlates with metastatic progression, reduced Maspin expression and infiltration of prostate tumours with RANKL-expressing inflammatory cells. We propose that tumour-infiltrating RANKL-expressing cells lead to nuclear IKK alpha activation and inhibition of Maspin transcription, thereby promoting the metastatic phenotype.