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
| Autor: | Kensuke Ohishi, Kazufumi Toume, Midori A. Arai, Masami Ishibashi, Takamasa Mizoguchi, Thaworn Kowithayakorn, Takashi Koyano, Motoyuki Itoh |
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| Rok vydání: | 2015 |
| Předmět: |
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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 |
| Zdroj: | Journal of Natural Products. 78:1139-1146 |
| ISSN: | 1520-6025 0163-3864 |
| DOI: | 10.1021/acs.jnatprod.5b00153 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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