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The nonsteroidal anti-inflammatory drugs aspirin and indomethacin attenuate β-catenin/TCF-4 signaling

Oncogene volume 20, pages 645–653 (2001)Cite this article

Abstract

Increasing epidemiological and experimental evidence implicates non-steroidal anti-inflammatory drugs (NSAIDs) as anti-tumorigenic agents. The precise mechanisms whereby NSAIDs exert their anti-neoplastic effects remain poorly understood. Studies from hereditary and sporadic colorectal cancer (CRC) patients suggest that NSAIDs may interfere with initiating steps of carcinogenesis, i.e. disturbances within the β-catenin signaling pathway. We therefore investigated β-catenin/TCF signaling in response to aspirin or indomethacin, respectively, in four CRC cell lines (SW948, SW480, HCT116, LoVo). Both, aspirin and indomethacin inhibited transcription of a β-catenin/TCF-responsive reporter gene in a dose dependent manner. In addition, the β-catenin/TCF transcriptional target cyclin D1 was downregulated by both drugs. Endogenous β-catenin levels remained unaffected by either drug. Moreover, indirect immunofluorescence studies revealed no significant changes of subcellular β-catenin localization in either cell line after NSAID treatment. Likewise, binding of the β-catenin/TCF complex to its specific DNA-binding sites was not altered, as demonstrated by electrophoretic mobility shift assay (EMSA) of nuclear extracts derived from NSAID treated cells. These results strongly suggest that aspirin and indomethacin attenuate the transcription of β-catenin/TCF-responsive genes, by modulating TCF activity without disrupting β-catenin/TCF complex formation.

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Acknowledgements

We are grateful to Hans Clevers, and KW Kinzler for reagents. This work was supported by a grant of the ‘Verein zur Förderung der Krebsforschung in Deutschland e.V’ to M von Knebel Doeberitz.

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  1. Division of Molecular Diagnostics and Therapy, Department of Surgery, University of Heidelberg, Heidelberg, D-69120, Germany

    Susanne Dihlmann, Anja Siermann & Magnus von Knebel Doeberitz

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Dihlmann, S., Siermann, A. & von Knebel Doeberitz, M. The nonsteroidal anti-inflammatory drugs aspirin and indomethacin attenuate β-catenin/TCF-4 signaling. Oncogene 20, 645–653 (2001). https://doi.org/10.1038/sj.onc.1204123

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