title: The β-catenin/TCF complex as a novel target of resveratrol in the Wnt/β-catenin signaling pathway.
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.
authors.affiliation: Graduate Institute of Molecular Systems Biomedicine, China Medical University, Taichung 404, Taiwan.
authors.forename: Hui-Jye
authors.initials: HJ
authors.lastname: Chen
authors.forename: Le-Shiang
authors.initials: LS
authors.lastname: Hsu
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Shia
authors.forename: Meng-Wei
authors.initials: MW
authors.lastname: Lin
authors.forename: Chung-Ming
authors.initials: CM
authors.lastname: Lin
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D011485:Protein Binding; D000077185:Resveratrol; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology*; D051820:TCF Transcription Factors / Q000378:metabolism*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D013267:Stilbenes; D051820:TCF Transcription Factors; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D000077185:Resveratrol