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

Jun Li Luo, Wei Tan, Jill M. Ricono, Olexandr Korchynskyi, Ming Zhang, Steven L. Gonias, David A. Cheresh, Michael Karin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

354 Scopus citations

Abstract

Inflammation enhances tumour promotion through NF-κB-dependent mechanisms. NF-κB was also proposed to promote metastatogenesis through epithelial-mesenchymal transition. 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 pregnancy. 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 epithelium. Decreased metastasis correlated with elevated expression of the metastasis suppressor Maspin, 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.

Original languageEnglish (US)
Pages (from-to)690-694
Number of pages5
JournalNature
Volume446
Issue number7136
DOIs
StatePublished - Apr 5 2007

ASJC Scopus subject areas

  • General

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