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ZFIN ID: ZDB-PUB-150424-2
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
Ohishi, K., Toume, K., Arai, M.A., Koyano, T., Kowithayakorn, T., Mizoguchi, T., Itoh, M., Ishibashi, M.
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.
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.