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

A Corrigendum to this article was published on 01 February 2009

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Abstract

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.

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Figure 1: IKKα activity is required for prostate cancer metastasis.
Figure 2: Maspin expression correlates with metastatogenesis.
Figure 3: Activated nuclear IKKα represses Maspin transcription.
Figure 4: Metastatic progression correlates with nuclear activation of IKKα, inflammatory cell infiltration and massive upregulation of RANKL.

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Change history

  • 01 February 2009

    Nature 446, 690–694 (2007) It has come to our attention that some of the control lanes in Fig. 2a (Kai1 and Mkk4 control lanes) may have been inadvertently duplicated during figure assembly; the other control lanes and the experimental Maspin lanes are correct. We have therefore repeated the experiments and obtained the same results as those in the published figure.

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Acknowledgements

J.-L.L. was supported by the Aventis-UICC Translational Cancer Research Fellowship, the Lopiccola Fellowship of the UCSD Cancer Center and the Life Science Research Fellowship. W.T. was supported by a postdoctoral fellowship from The Susan G. Komen Breast Cancer Foundation. Work in M.K.’s laboratory was supported by grants from the NIH, the US Army Medical Research and Materiel Command and the Prostate Cancer Foundation. M.K. is an American Cancer Society Research Professor. We thank M. Stampfer for HME cells, S. Srivastava and Z. Khalkhali-Ellis for Maspin–luciferase reporters and H. R. Li for assistance with the statistical analysis.

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This file contains Supplementary Methods, Supplementary Figures S1-S9 with Legends, Supplementary Table 1 and additional references. (PDF 3646 kb)

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Luo, JL., Tan, W., Ricono, J. et al. Nuclear cytokine-activated IKKα controls prostate cancer metastasis by repressing Maspin. Nature 446, 690–694 (2007). https://doi.org/10.1038/nature05656

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