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Letter

Nature 446, 690-694 (5 April 2007) | doi:10.1038/nature05656; Received 5 December 2006; Accepted 2 February 2007; Published online 18 March 2007

There is a Corrigendum (12 February 2009) associated with this document.

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

Jun-Li Luo1, Wei Tan1, Jill M. Ricono2, Olexandr Korchynskyi1, Ming Zhang3, Steven L. Gonias2, David A. Cheresh2 & Michael Karin1

  1. Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Cancer Center, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0723, USA
  2. Department of Pathology and the Moores Cancer Center, University of California, San Diego, La Jolla, California 92093-0803, USA
  3. Baylor College of Medicine, Department of Molecular and Cellular Biology, One Baylor Plaza, Houston, Texas 77030, USA

Correspondence to: Michael Karin1 Correspondence and requests for materials should be addressed to M.K. (Email: karinoffice@ucsd.edu).

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Inflammation enhances tumour promotion through NF-kappaB-dependent mechanisms1. NF-kappaB 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 IkappaB kinase alpha (IKKalpha), activated by receptor activator of NF-kappaB (RANK/TNFRSF11A), in mammary epithelial proliferation during pregnancy3. Owing to similarities between mammary and prostate epithelia, we examined IKKalpha involvement in prostate cancer and its progression. Here we show that a mutation that prevents IKKalpha 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. IKKalpha activation by RANK ligand (RANKL/TNFSF11) inhibits Maspin expression in prostate epithelial cells, whereas repression of Maspin transcription requires nuclear translocation of active IKKalpha. The amount of active nuclear IKKalpha 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 IKKalpha activation and inhibition of Maspin transcription, thereby promoting the metastatic phenotype.