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Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12584-9. Epub 2003 Oct 17.

Nitric oxide-donating aspirin inhibits beta-catenin/T cell factor (TCF) signaling in SW480 colon cancer cells by disrupting the nuclear beta-catenin-TCF association.

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1
Department of Physiology and Pharmacology, City University of New York Medical School, New York, NY 10031.

Abstract

Dysregulation of the Wnt pathway and altered Beta-catenin expression are central early events in colorectal carcinogenesis. We studied the ortho, meta, and para (o-, m-, and p-) positional isomers of NO-donating aspirin (NO-ASA), a chemopreventive agent against colon cancer, for their effect on Beta-catenin/T cell factor (TCF) signaling. In human SW480 colon carcinoma cells, cell-growth inhibition by NO-ASA [IC50 values for p-, o-, and m- were 48.1 +/- 4.3 (mean +/-SEM), 60.4 +/- 2.1, and 900 +/-50 microM, respectively] was accompanied by significant inhibition of Beta-catenin signaling. We determined Beta-catenin-dependent TCF-4 transcriptional activity by measuring the activity of the luciferase gene placed under the control of TCF-4 regulatory sequences. The IC50 values for Beta-catenin/TCF-4-signaling inhibition by NO-ASA were: o-, 2.6 +/- 0.4; m-, 15 +/- 5; p-, 1.1 +/- 0.1 microM; and for ASA, >5,000 microM. Total or nuclear levels of Beta-catenin and its distribution in the cell were not altered by NO-ASA, as judged by protein expression levels and semiquantitative immunofluorescence analysis. NO-ASA disrupted the association of Beta-catenin and TCF-4 in the nucleus, whereas ASA did not affect it. NO-ASA reduced the expression of cyclin D1, a downstream target gene that plays an important role in colon carcinogenesis. In contrast, a structural analog of NO-ASA lacking the -NO2 moiety did not affect TCF-4 transcriptional activity. Thus, NO-ASA inhibits Beta-catenin-mediated TCF activity by preventing the formation of the Beta-catenin/TCF-4 complex. This effect, occurring at NO-ASA concentrations far below those required to inhibit cell growth, may be a critical early event in the chemopreventive activity of NO-ASA against colon cancer.

PMID:
14566053
PMCID:
PMC240661
DOI:
10.1073/pnas.2134840100
[Indexed for MEDLINE]
Free PMC Article
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