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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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.
References
Karin, M. Nuclear factor-κB in cancer development and progression. Nature 441, 431–436 (2006)
Huber, M. A. et al. NF-κB is essential for epithelial–mesenchymal transition and metastasis in a model of breast cancer progression. J. Clin. Invest. 114, 569–581 (2004)
Cao, Y. et al. IKKα provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development. Cell 107, 763–775 (2001)
Greenberg, N. M. et al. Prostate cancer in a transgenic mouse. Proc. Natl Acad. Sci. USA 92, 3439–3443 (1995)
Zou, Z. et al. Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells. Science 263, 526–529 (1994)
DeMarzo, A. M., Nelson, W. G., Isaacs, W. B. & Epstein, J. I. Pathological and molecular aspects of prostate cancer. Lancet 361, 955–964 (2003)
Montironi, R., Mazzucchelli, R., Scarpelli, M., Lopez-Beltran, A. & Mikuz, G. Prostate carcinoma I: prognostic factors in radical prostatectomy specimens and pelvic lymph nodes. BJU Int. 97, 485–491 (2006)
Karin, M., Yamamoto, Y. & Wang, Q. M. The IKK NF-κB system: a treasure trove for drug development. Nature Rev. Drug Discov. 3, 17–26 (2004)
DiDonato, J. A., Hayakawa, M., Rothwarf, D. M., Zandi, E. & Karin, M. A cytokine-responsive IκB kinase that activates the transcription factor NF-κB. Nature 388, 548–554 (1997)
Kaplan-Lefko, P. J. et al. Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model. Prostate 55, 219–237 (2003)
Chuang, C. K., Wu, T. L., Tsao, K. C. & Liao, S. K. Elevated serum chromogranin A precedes prostate-specific antigen elevation and predicts failure of androgen deprivation therapy in patients with advanced prostate cancer. J. Formos. Med. Assoc. 102, 480–485 (2003)
Steeg, P. S. Metastasis suppressors alter the signal transduction of cancer cells. Nature Rev. Cancer 3, 55–63 (2003)
Zhang, M. et al. Maspin plays an important role in mammary gland development. Dev. Biol. 215, 278–287 (1999)
Zhang, M., Shi, Y., Magit, D., Furth, P. A. & Sager, R. Reduced mammary tumor progression in WAP-TAg/WAP-maspin bitransgenic mice. Oncogene 19, 6053–6058 (2000)
Zou, Z. et al. Maspin expression profile in human prostate cancer (CaP) and in vitro induction of Maspin expression by androgen ablation. Clin. Cancer Res. 8, 1172–1177 (2002)
Cher, M. L. et al. Maspin expression inhibits osteolysis, tumor growth, and angiogenesis in a model of prostate cancer bone metastasis. Proc. Natl Acad. Sci. USA 100, 7847–7852 (2003)
Lockett, J., Yin, S., Li, X., Meng, Y. & Sheng, S. Tumor suppressive maspin and epithelial homeostasis. J. Cell. Biochem. 97, 651–660 (2006)
Senftleben, U. et al. Activation by IKKα of a second, evolutionary conserved, NF-κB signaling pathway. Science 293, 1495–1499 (2001)
Stupack, D. G. et al. Potentiation of neuroblastoma metastasis by loss of caspase-8. Nature 439, 95–99 (2006)
Zou, Z. et al. p53 regulates the expression of the tumor suppressor gene maspin. J. Biol. Chem. 275, 6051–6054 (2000)
Sil, A. K., Maeda, S., Sano, Y., Roop, D. R. & Karin, M. IκB kinase-α acts in the epidermis to control skeletal and craniofacial morphogenesis. Nature 428, 660–664 (2004)
Bonizzi, G. et al. Activation of IKKα target genes depends on recognition of specific κB binding sites by RelB:p52 dimers. EMBO J. 23, 4202–4210 (2004)
Ruocco, M. G. et al. IκB kinase (IKK)β, but not IKKα, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss. J. Exp. Med. 201, 1677–1687 (2005)
Balkwill, F., Charles, K. A. & Mantovani, A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7, 211–217 (2005)
Chen, E. I. & Yates, J. R. Maspin and tumor metastasis. IUBMB Life 58, 25–29 (2006)
Sato, N., Fukushima, N., Matsubayashi, H. & Goggins, M. Identification of maspin and S100P as novel hypomethylation targets in pancreatic cancer using global gene expression profiling. Oncogene 23, 1531–1538 (2004)
Di Croce, L. et al. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295, 1079–1082 (2002)
Jones, D. H. et al. Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440, 692–696 (2006)
Luo, J. L., Maeda, S., Hsu, L. C., Yagita, H. & Karin, M. Inhibition of NF-κB in cancer cells converts inflammation- induced tumor growth mediated by TNFα to TRAIL-mediated tumor regression. Cancer Cell 6, 297–305 (2004)
Morimoto-Tomita, M., Ohashi, Y., Matsubara, A., Tsuiji, M. & Irimura, T. Mouse colon carcinoma cells established for high incidence of experimental hepatic metastasis exhibit accelerated and anchorage-independent growth. Clin. Exp. Metastasis 22, 513–521 (2005)
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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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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DOI: https://doi.org/10.1038/nature05656
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