Carcinogenesis Advance Access published online on December 20, 2006
Carcinogenesis, doi:10.1093/carcin/bgl254
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Docosahexaenoic Acid Induces Proteasome-dependent Degradation of ß-catenin, Down-regulation of Survivin and Apoptosis in Human Colorectal Cancer Cells not expressing COX-2
1 Institutes of General Pathology, Human Anatomy, Catholic University – L.go F. Vito, 1 – 00168 Rome, Italy
2 Institutes of General Pathology, Histology, Catholic University – L.go F. Vito, 1 – 00168 Rome, Italy
* To whom correspondence should be addressed. E-mail: g.calviello{at}rm.unicatt.it
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 COX-2 expression. Since dysregulation of ß-catenin expression is frequently found at early stage of colorectal carcinogenesis, we analyzed whether docosahexaenoic acid (DHA) may modify the expression of ß-catenin in colon cancer cells (SW480 and HCT116) overexpressing this protein, but lacking COX-2. Futhermore, we investigated if alterations in ß-catenin expression may be associated with apoptosis induction. Treatment of cells with increasing concentrations of DHA induced a dose- and time-dependent inhibition of ß-catenin protein expression which, however, was not accompanied by modifications in ß-catenin transcription. Conversely, the proteasomal inhibitors MG132 and lactacystin prevented DHA-induced ß-catenin decrease, suggesting that DHA may regulate the proteasomal degradation of ß-catenin. The reduced levels of ß-catenin were accompanied by decreased translocation of ß-catenin into the nucleus, where it acts as a transcription factor in concert with 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/ß-catenin stimulation. Several other proteins regulated by the TCF/ß-catenin pathway and involved in regulation of tumor growth were down-regulated by DHA, including PPAR-
, MT1-MMP, MMP-7, and VEGF. The present study, thus, raises the possibility that DHA may exert pro-apoptotic and antitumoral effects through proteasomal regulation of ß-catenin levels and alterations in the expression of TCF/ß-catenin-target genes.
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