PUBLICATION

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

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
  • Animals
  • Blotting, Western
  • Carbolines/chemistry
  • Carbolines/isolation & purification*
  • Carbolines/pharmacology*
  • Casein Kinase Ialpha/metabolism*
  • Eurycoma/chemistry*
  • Glycogen Synthase Kinase 3/drug effects
  • Glycogen Synthase Kinase 3/metabolism*
  • HCT116 Cells
  • Humans
  • Indole Alkaloids/chemistry
  • Indole Alkaloids/isolation & purification*
  • Indole Alkaloids/pharmacology*
  • Luciferases/metabolism
  • Plant Roots/chemistry
  • Thailand
  • Wnt Signaling Pathway/drug effects*
  • Zebrafish
  • beta Catenin/analysis
  • beta Catenin/drug effects
PubMed
25905468 Full text @ J. Nat. Prod.
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
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping