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

Gabriella Calviello, Simona Serini, Amelia Toesca Di Castellazzo, Giovanni Monego, Elisabetta Piccioni, Alma Boninsegna Lucarelli, Franco Oreste Ranelletti, Paola Palozza, Federica Resci

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94 Citazioni (Scopus)

Abstract

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 beta-catenin expression is frequently found at early stage of colorectal carcinogenesis, we analyzed whether docosahexaenoic acid (DHA) may modify the expression of beta-catenin in colon cancer cells (SW480 and HCT116) overexpressing this protein, but lacking COX-2. Futhermore, we investigated if alterations in beta-catenin expression may be associated with apoptosis induction. Treatment of cells with increasing concentrations of DHA induced a dose- and time-dependent inhibition of beta-catenin protein expression which, however, was not accompanied by modifications in beta-catenin transcription. Conversely, the proteasomal inhibitors MG132 and lactacystin prevented DHA-induced beta-catenin decrease, suggesting that DHA may regulate the proteasomal degradation of beta-catenin. The reduced levels of beta-catenin were accompanied by decreased translocation of beta-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/beta-catenin stimulation. Several other proteins regulated by the TCF/beta-catenin pathway and involved in regulation of tumor growth were down-regulated by DHA, including PPAR-delta, 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 beta-catenin levels and alterations in the expression of TCF/beta-catenin-target genes.
Lingua originaleEnglish
pagine (da-a)1202-1209
Numero di pagine8
RivistaCarcinogenesis
DOI
Stato di pubblicazionePubblicato - 2007

Keywords

  • COX-2
  • Docosaesaenoic acid
  • beta-catenin
  • colon cancer

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