Carcinogenesis Advance Access originally published online on December 20, 2006
Carcinogenesis 2007 28(6):1202-1209; 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
Institute of General Pathology, 1 Institute of Human Anatomy
2 Institute of Histology, Catholic University—L.go F. Vito, 1—00168 Rome, Italy
* To whom correspondence should be addressed. Tel: +39 06 3016619; Fax: +39 06 3386446; 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 cycloxygenase-2 (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) over-expressing 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 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–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 peroxisome proliferator-activated receptor-
, 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 ß-catenin levels and alterations in the expression of TCF–ß-catenin target genes.
Abbreviations: APC, adenomatous polyposis coli; COX-2, cyclooxygenase-2; DHA, docosahexaenoic acid; FITC, fluorescein isothiocyanate; HIF-1, hypoxia-inducible factor-1; MMP-7, matrix metalloproteinase-7; MT1, membrane type 1; PBS, phosphate-buffered saline; pERK, phosphorylated extracellular regulated protein kinase; PGE2, prostaglandin E2; PUFA, polyunsaturated fatty acid; RT–PCR, reverse transcription–polymerase chain reaction; TCF, T-Cell Factor; VEGF, vascular endothelial growth factor
Received October 12, 2006; revised December 7, 2006; accepted December 15, 2006.
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