Journal Article

Docosahexaenoic acid induces proteasome-dependent degradation of β-catenin, down-regulation of survivin and apoptosis in human colorectal cancer cells not expressing COX-2

Gabriella Calviello, Federica Resci, Simona Serini, Elisabetta Piccioni, Amelia Toesca, Alma Boninsegna, Giovanni Monego, Franco O. Ranelletti and Paola Palozza

in Carcinogenesis

Volume 28, issue 6, pages 1202-1209
Published in print June 2007 | ISSN: 0143-3334
Published online December 2006 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgl254
Docosahexaenoic acid induces proteasome-dependent degradation of β-catenin, down-regulation of survivin and apoptosis in human colorectal cancer cells not expressing COX-2

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n-3 Polyunsaturated fatty acids have been shown to powerfully inhibit the growth of colon cancer cells, mainly acting as pro-apoptotic agents through inhibition of cycloxygenase-2 (COX-2) expression. Since dysregulation of β-catenin expression is frequently found at early stage of colorectal carcinogenesis, we analyzed whether docosahexaenoic acid (DHA) may modify the expression of β-catenin in colon cancer cells (SW480 and HCT116) over-expressing this protein, but lacking COX-2. Futhermore, we investigated if alterations in β-catenin expression may be associated with apoptosis induction. Treatment of cells with increasing concentrations of DHA induced a dose- and time-dependent inhibition of β-catenin protein expression which, however, was not accompanied by modifications in β-catenin transcription. Conversely, the proteasomal inhibitors MG132 and lactacystin prevented DHA-induced β-catenin decrease, suggesting that DHA may regulate the proteasomal degradation of β-catenin. The reduced levels of β-catenin were accompanied by decreased translocation of β-catenin into the nucleus, where it acts as a transcription factor in concert with T-Cell Factor (TCF). DHA, at the same range of concentrations, was also able to induce apoptosis by a caspase-3-dependent mechanism and to cause a dose- and time-dependent decrease of survivin, an apoptosis inhibitor undetectable in normal tissues and expressed in colorectal cancer through TCF–β-catenin stimulation. Several other proteins regulated by the TCF–β-catenin pathway and involved in regulation of tumor growth were down-regulated by DHA, including peroxisome proliferator-activated receptor-δ, membrane type 1 (MT1)-matrix metalloproteinase (MMP), MMP-7 and vascular endothelial growth factor. The present study, thus, raises the possibility that DHA may exert pro-apoptotic and antitumoral effects through proteasomal regulation of β-catenin levels and alterations in the expression of TCF–β-catenin target genes.

Journal Article.  5958 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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