Nitric Oxide-Induced Down-Regulation of β-Catenin in Colon Cancer Cells by a Proteasome-Independent Specific Pathway

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Abstract

Background & Aims: We have previously reported that nitric oxide could induce the death of colon cancer cells. Because an inappropriate activation of β-catenin has been associated with intestinal cell malignant transformation, we explored whether nitric oxide could affect β-catenin expression and function. Methods: Human colon cancer cell lines were treated with the nitric oxide donor glyceryl trinitrate (GTN) before analyzing β-catenin expression by immunofluorescence, immunoblotting, and immunoprecipitation methods and its transcriptional activity using a luciferase reporter gene driven by a T-cell factor-responsive promotor. Results: GTN induces β-catenin degradation and down-regulates its transcriptional activity in colon cancer cells. This effect is preceded by GTN-induced tyrosine nitration of β-catenin, together with its dephosphorylation on serine 33, 37, and 45 and threonine 41. GTN-induced β-catenin degradation involves proteases that are sensitive to a broad-spectrum caspase inhibitor, z-VAD-fmk, and to serine protease inhibitors N-tosyl-L-phenylalaline chloromethyl ketone (TPCK) and [4-(2-aminoethyl)-benzenesulfonylfluoride] (AEBSF), whereas the ubiquitin/proteasome pathway is not involved. Interestingly, only TPCK and AEBSF restore β-catenin transcriptional activity and preserve β-catenin nuclear localization in GTN-treated colon cancer cells. Conclusions: Exposure of colon cancer cells to nitric oxide unraveled a so-far-unidentified mechanism of β-catenin regulation. The protein is nitrated and dephosphorylated, and its transcriptional activity is reduced through degradation by a TPCK and AEBSF-sensitive protease. © 2006 American Gastroenterological Association (AGA) Institute.

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Prévotat, L., Filomenko, R., Solary, E., Jeannin, J. F., & Bettaieb, A. (2006). Nitric Oxide-Induced Down-Regulation of β-Catenin in Colon Cancer Cells by a Proteasome-Independent Specific Pathway. Gastroenterology, 131(4), 1142–1152. https://doi.org/10.1053/j.gastro.2006.07.017

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