Abstract
Understanding the mechanisms that underlie the antitumour activity of non-steroidal anti-inflammatory drugs (NSAIDs) against colorectal cancer will allow the development of more effective and specific chemopreventative agents. Modulation of the NF-κB pathway has been implicated as a key effector of the antitumour effect of aspirin, but the effects of non-aspirin NSAIDs on this pathway have yet to be fully defined. Here, we demonstrate that sulindac, sulindac sulfone and indomethacin activate the NF-κB pathway in colorectal cancer cells, as determined by western blot analysis of cytoplasmic levels of IκBα and immunocytochemical analysis of nuclear NF-κB/RelA. Furthermore, we show that all of these NSAIDs induce nucleolar translocation of the RelA subunit of NF-κB. Using RelA deleted for the previously described nucleolar localization signal, we demonstrate that this response is causally involved in the apoptotic effects of these agents. Finally, we demonstrate that NSAID-mediated nucleolar translocation of RelA is associated with downregulation of NF-κB-driven transcription and of the NF-κB target gene, ICAM-1. These data identify nucleolar translocation of RelA and the associated repression of the NF-κB-driven transcription as a central molecular mechanism of NSAID-mediated growth inhibition and apoptosis. As well as providing new understanding of the molecular determinants of RelA function, these findings also have relevance to the development of novel chemotherapeutic and chemopreventative agents.
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Acknowledgements
We gratefully acknowledge the gifts from Ron T Hay (University of Dundee) of the IκBα antibody and the 3enhancer CON-A luciferase reporter constructs. We also thank E Quarnstrom (University of Sheffield) for kindly providing the RelA-GFP expression vector and T Parks (Netherlands Institute for Developmental Biology) for providing the ICAM-1 luciferase reporter construct. The work was supported by grants from the Scottish Executive Chief Scientist's Office (K/MRS/50/C2719 and CZB/4/41) the AICR (02-330) and Cancer Research UK (C20658/A6656). MGD is supported by Cancer Research UK Programme Grant funding (C348/A3758 and C48/A6361).
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Loveridge, C., MacDonald, A., Thoms, H. et al. The proapoptotic effects of sulindac, sulindac sulfone and indomethacin are mediated by nucleolar translocation of the RelA(p65) subunit of NF-κB. Oncogene 27, 2648–2655 (2008). https://doi.org/10.1038/sj.onc.1210891
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DOI: https://doi.org/10.1038/sj.onc.1210891
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