Docosahexaenoic acid induces proteasome-dependent degradation of beta-catenin, downregulation of survivin and apoptosis in human colorectal cancer cells not expressing COX-2.

n-3 Polyunsaturated fatty acids have been shown to powerfully inhibit the growth\r\nof colon cancer cells, mainly acting as pro-apoptotic agents through inhibition\r\nof COX-2 expression. Since dysregulation of beta-catenin expression is\r\nfrequently found at early stage of colorectal carcinogenesis, we analyzed\r\nwhether docosahexaenoic acid (DHA) may modify the expression of beta-catenin in\r\ncolon cancer cells (SW480 and HCT116) overexpressing this protein, but lacking\r\nCOX-2. Futhermore, we investigated if alterations in beta-catenin expression may\r\nbe associated with apoptosis induction. Treatment of cells with increasing\r\nconcentrations of DHA induced a dose- and time-dependent inhibition of\r\nbeta-catenin protein expression which, however, was not accompanied by\r\nmodifications in beta-catenin transcription. Conversely, the proteasomal\r\ninhibitors MG132 and lactacystin prevented DHA-induced beta-catenin decrease,\r\nsuggesting that DHA may regulate the proteasomal degradation of beta-catenin.\r\nThe reduced levels of beta-catenin were accompanied by decreased translocation\r\nof beta-catenin into the nucleus, where it acts as a transcription factor in\r\nconcert with TCF. DHA, at the same range of concentrations, was also able to\r\ninduce apoptosis by a caspase-3 dependent mechanism and to cause a dose- and\r\ntime-dependent decrease of survivin, an apoptosis inhibitor undetectable in\r\nnormal tissues and expressed in colorectal cancer through TCF/beta-catenin\r\nstimulation. Several other proteins regulated by the TCF/beta-catenin pathway\r\nand involved in regulation of tumor growth were down-regulated by DHA, including\r\nPPAR-delta, MT1-MMP, MMP-7, and VEGF. The present study, thus, raises the\r\npossibility that DHA may exert pro-apoptotic and antitumoral effects through\r\nproteasomal regulation of beta-catenin levels and alterations in the expression\r\nof TCF/beta-catenin-target genes.