1. 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
- Author
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Kensuke Ohishi, Kazufumi Toume, Midori A. Arai, Masami Ishibashi, Takamasa Mizoguchi, Thaworn Kowithayakorn, Takashi Koyano, and Motoyuki Itoh
- Subjects
Blotting, Western ,Pharmaceutical Science ,Biology ,Plant Roots ,Indole Alkaloids ,Analytical Chemistry ,Glycogen Synthase Kinase 3 ,GSK-3 ,Drug Discovery ,Animals ,Humans ,Luciferase ,Eurycoma ,Luciferases ,Wnt Signaling Pathway ,GSK3B ,Zebrafish ,beta Catenin ,Pharmacology ,Glycogen Synthase Kinase 3 beta ,Cell growth ,Organic Chemistry ,Wnt signaling pathway ,Casein Kinase Ialpha ,LRP5 ,HCT116 Cells ,Thailand ,Molecular biology ,Complementary and alternative medicine ,Molecular Medicine ,Phosphorylation ,Casein kinase 1 ,Carbolines - 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.
- Published
- 2015