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Biochem Pharmacol. 2012 Nov 1;84(9):1143-53. doi: 10.1016/j.bcp.2012.08.011. Epub 2012 Aug 19.

The β-catenin/TCF complex as a novel target of resveratrol in the Wnt/β-catenin signaling pathway.

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1
Graduate Institute of Molecular Systems Biomedicine, China Medical University, Taichung 404, Taiwan.

Abstract

Wnts are secreted glycolipoproteins that play important roles in the regulation of embryonic development and tissue homeostasis. Binding of Wnt to receptors and co-receptors causes inactivation of the β-catenin destruction complex, which leads to the stabilization and nuclear translocation of β-catenin to initiate Wnt-responsive gene expression after associating with TCF in the nucleus. As its deregulation results in serious human diseases, especially cancers, the Wnt signaling pathway serves as a promising platform for screening anti-cancer drugs. Resveratrol was selected based on its ability to inhibit the β-catenin/TCF-mediated transcriptional activity. Resveratrol, a natural phytoalexin found in a variety of plants, possesses health-promoting properties including anti-aging, anti-inflammatory, anti-oxidant, anti-cancer, cardioprotective and neuroprotective activities. We found that resveratrol indeed exhibited dose-dependent suppression of Wnt signaling, reduced the expression of Wnt target genes such as cyclin D1 and conductin, and inhibited the growth of Wnt-stimulated cells and Wnt-driven colorectal cancer cells. Further studies indicated that resveratrol functions downstream of GSK3β. Treatment with resveratrol did not alter the amount of β-catenin and its distribution in the cytoplasm and nucleus, suggesting that resveratrol did not affect the accumulation and nuclear targeting of β-catenin. In contrast, co-immunoprecipitation and in vitro binding analyses substantiated that resveratrol was capable of disrupting the binding between β-catenin and TCF4, contributing to the decreased Wnt signaling. Our discoveries not only reveal a novel target of resveratrol in the Wnt signaling pathway but also show the potential of therapy with harmless resveratrol in colorectal cancer and other Wnt-related diseases.

PMID:
22935447
DOI:
10.1016/j.bcp.2012.08.011
[Indexed for MEDLINE]
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