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

TLDR: It is proposed that tumour-infiltrating RANKL-expressing cells lead to nuclear IKKα activation and inhibition of Maspin transcription, thereby promoting the metastatic phenotype.

Abstract: Experiments in a mouse prostate cancer model have identified a signalling pathway that stimulates the formation of metastases. The pathway is initiated when a protein ligand occupies a receptor known as RANK (receptor activator of nuclear factor κB), and is dependent on the activation and nuclear translocation of IKKα (IκB kinase α). Once in the nucleus, activated IKKα represses maspin gene transcription, whose product is well established as an inhibitor of cell migration and invasion in prostate and breast cancer. RANK may therefore be a general promoter of metastatic behaviour in prostate or mammary carcinoma cells. A previously unknown signalling pathway is shown to enhance the formation of metastases in a mouse model of prostate cancer. This pathway can be activated by RANK ligand that is expressed by inflammatory cells in the tumour and triggers activation of IKKα in the nucleus, where it directly represses the transcription of maspin, a known metastases suppressor. Inflammation enhances tumour promotion through NF-κB-dependent mechanisms1. NF-κB was also proposed to promote metastatogenesis through epithelial–mesenchymal transition2. Yet a mechanistic link between inflammation and metastasis is missing. We identified a role for IκB kinase α (IKKα), activated by receptor activator of NF-κB (RANK/TNFRSF11A), in mammary epithelial proliferation during pregnancy3. Owing to similarities between mammary and prostate epithelia, we examined IKKα involvement in prostate cancer and its progression. Here we show that a mutation that prevents IKKα activation slows down CaP growth and inhibits metastatogenesis in TRAMP mice, which express SV40 T antigen in the prostate epithelium4. Decreased metastasis correlated with elevated expression of the metastasis suppressor Maspin5, the ablation of which restored metastatic activity. IKKα activation by RANK ligand (RANKL/TNFSF11) inhibits Maspin expression in prostate epithelial cells, whereas repression of Maspin transcription requires nuclear translocation of active IKKα. The amount of active nuclear IKKα 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 IKKα activation and inhibition of Maspin transcription, thereby promoting the metastatic phenotype.