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.

Calviello, G., Resci, F., Serini, S., Piccioni, E., Toesca Di Castellazzo, A., Boninsegna Lucarelli, A., Monego, G., Ranelletti, F. O., Palozza, P., Docosahexaenoic acid induces proteasome-dependent degradation of beta-catenin, downregulation of survivin and apoptosis in human colorectal cancer cells not expressing COX-2., <<CARCINOGENESIS>>, 2007; (Giugno): 1202-1209. [doi:10.1093/carcin/bgl254] [http://hdl.handle.net/10807/20950]

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

Calviello, Gabriella;Serini, Simona;Piccioni, Elisabetta;Toesca Di Castellazzo, Amelia;Boninsegna Lucarelli, Alma;Monego, Giovanni;Ranelletti, Franco Oreste;Palozza, Paola
2007

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.
Inglese
Calviello, G., Resci, F., Serini, S., Piccioni, E., Toesca Di Castellazzo, A., Boninsegna Lucarelli, A., Monego, G., Ranelletti, F. O., Palozza, P., Docosahexaenoic acid induces proteasome-dependent degradation of beta-catenin, downregulation of survivin and apoptosis in human colorectal cancer cells not expressing COX-2., <<CARCINOGENESIS>>, 2007; (Giugno): 1202-1209. [doi:10.1093/carcin/bgl254] [http://hdl.handle.net/10807/20950]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/20950
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