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- Title
The nonsteroidal anti-inflammatory drugs aspirin and indomethacin attenuate β-catenin/TCF-4 signaling.
- Authors
Dihlmann, Susanne; Siermann, Anja; von Knebel Doeberitz, Magnus
- 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. Oncogene (2001) 20, 645–653.
- Subjects
ASPIRIN; COLON cancer; TUMORS
- Publication
Oncogene, 2001, Vol 20, Issue 5, p645
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1204123