title: 9-Hydroxycanthin-6-one, a β-Carboline Alkaloid from Eurycoma longifolia, Is the First Wnt Signal Inhibitor through Activation of Glycogen Synthase Kinase 3β without Depending on Casein Kinase 1α.
abstract: Wnt signaling regulates various processes such as cell proliferation, differentiation, and embryo development. However, numerous diseases have been attributed to the aberrant transduction of Wnt signaling. We screened a plant extract library targeting TCF/β-catenin transcriptional modulating activity with a cell-based luciferase assay. Activity-guided fractionation of the MeOH extract of the E. longifolia root led to the isolation of 9-hydroxycanthin-6-one (1). Compound 1 exhibited TCF/β-catenin inhibitory activity. Compound 1 decreased the expression of Wnt signal target genes, mitf and zic2a, in zebrafish embryos. Treatment of SW480 cells with 1 decreased β-catenin and increased phosphorylated β-catenin (Ser 33, 37, Tyr 41) protein levels. The degradation of β-catenin by 1 was suppressed by GSK3β-siRNA, while compound 1 decreased β-catenin even in the presence of CK1α-siRNA. These results suggest that 1 inhibits Wnt signaling through the activation of GSK3β independent of CK1α.
authors.affiliation: †Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Ohishi
authors.affiliation: †Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Toume
authors.affiliation: †Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Midori A
authors.initials: MA
authors.lastname: Arai
authors.affiliation: ‡Temko Corporation, 4-27-4 Honcho, Nakano, Tokyo 164-0012, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Koyano
authors.affiliation: §Faculty of Agriculture, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Thaworn
authors.initials: T
authors.lastname: Kowithayakorn
authors.affiliation: †Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Mizoguchi
authors.affiliation: †Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Itoh
authors.affiliation: †Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Ishibashi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002243:Carbolines / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D048128:Casein Kinase Ialpha / Q000378:metabolism*; D035701:Eurycoma / Q000737:chemistry*; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D045325:HCT116 Cells; D006801:Humans; D026121:Indole Alkaloids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D018517:Plant Roots / Q000737:chemistry; D013785:Thailand; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D015027:Zebrafish; D051176:beta Catenin / Q000032:analysis / Q000187:drug effects
chemical_list: C574274:9-hydroxycanthin-6-one; D002243:Carbolines; D026121:Indole Alkaloids; D051176:beta Catenin; D008156:Luciferases; D048128:Casein Kinase Ialpha; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3