title: Galangin suppresses the proliferation of β-catenin response transcription-positive cancer cells by promoting adenomatous polyposis coli/Axin/glycogen synthase kinase-3β-independent β-catenin degradation.
abstract: Galangin is a naturally occurring bioflavonoid with anticancer activity against certain human cancers, yet little is known about its mechanism of action. Here, we used a chemical biology approach to reveal that galangin suppresses β-catenin response transcription (CRT), which is aberrantly up-regulated in colorectal and liver cancers, by promoting the degradation of intracellular β-catenin. Inhibition of glycogen synthase kinase-3β (GSK-3β) activity or mutation of the GSK-3β-targeted sequence from β-catenin was unable to abrogate the galangin-mediated degradation of β-catenin. In addition, galangin down-regulated the intracellular β-catenin levels in cancer cells with inactivating mutations of adenomatous polyposis coli (APC) or Axin, which are components of the β-catenin destruction complex. Galangin repressed the expression of β-catenin/T-cell factor-dependent genes, such as cyclin D1 and c-myc, and thus inhibited the proliferation of CRT-positive cancer cells. Structure-activity data indicated that the major structural requirements for galangin-mediated β-catenin degradation are hydroxyl groups at positions 3, 5, and 7. Our findings suggest that galangin exerts its anticancer activity by promoting APC/Axin/GSK-3β-independent proteasomal degradation of β-catenin.
authors.affiliation: PharmacoGenomics Research Center, Inje University, Busan, Korea.
authors.forename: Jungsug
authors.initials: J
authors.lastname: Gwak
authors.forename: Jingyo
authors.initials: J
authors.lastname: Oh
authors.forename: Munju
authors.initials: M
authors.lastname: Cho
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Bae
authors.forename: Im-Sook
authors.initials: IS
authors.lastname: Song
authors.forename: Kwang-Hyeon
authors.initials: KH
authors.lastname: Liu
authors.forename: Yongsu
authors.initials: Y
authors.lastname: Jeong
authors.forename: Dong-Eun
authors.initials: DE
authors.lastname: Kim
authors.forename: Young-Hwa
authors.initials: YH
authors.lastname: Chung
authors.forename: Sangtaek
authors.initials: S
authors.lastname: Oh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D060466:Axin Protein; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006868:Hydrolysis; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C555337:APC protein, human; D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; D005419:Flavonoids; D012097:Repressor Proteins; D051176:beta Catenin; C037032:galangin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3