PUBLICATION
9-Hydroxycanthin-6-one, a ?-Carboline Alkaloid from Eurycoma longifolia, Is the First Wnt Signal Inhibitor through Activation of Glycogen Synthase Kinase 3? without Depending on Casein Kinase 1?
- Authors
- Ohishi, K., Toume, K., Arai, M.A., Koyano, T., Kowithayakorn, T., Mizoguchi, T., Itoh, M., Ishibashi, M.
- ID
- ZDB-PUB-150424-2
- Date
- 2015
- Source
- Journal of natural products 78(5): 1139-46 (Journal)
- Registered Authors
- Itoh, Motoyuki, Mizoguchi, Takamasa
- Keywords
- none
- MeSH Terms
-
- Humans
- Blotting, Western
- Zebrafish
- Glycogen Synthase Kinase 3/drug effects
- Glycogen Synthase Kinase 3/metabolism*
- Eurycoma/chemistry*
- Carbolines/chemistry
- Carbolines/isolation & purification*
- Carbolines/pharmacology*
- Luciferases/metabolism
- Casein Kinase Ialpha/metabolism*
- Wnt Signaling Pathway/drug effects*
- Thailand
- Plant Roots/chemistry
- HCT116 Cells
- Indole Alkaloids/chemistry
- Indole Alkaloids/isolation & purification*
- Indole Alkaloids/pharmacology*
- Animals
- beta Catenin/analysis
- beta Catenin/drug effects
- PubMed
- 25905468 Full text @ J. Nat. Prod.
Citation
Ohishi, K., Toume, K., Arai, M.A., Koyano, T., Kowithayakorn, T., Mizoguchi, T., Itoh, M., Ishibashi, M. (2015) 9-Hydroxycanthin-6-one, a ?-Carboline Alkaloid from Eurycoma longifolia, Is the First Wnt Signal Inhibitor through Activation of Glycogen Synthase Kinase 3? without Depending on Casein Kinase 1?. Journal of natural products. 78(5):1139-46.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping