2. Academic Validation
  3. 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

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

  • J Nat Prod. 2015 May 22;78(5):1139-46. doi: 10.1021/acs.jnatprod.5b00153.
Kensuke Ohishi 1,  Kazufumi Toume 1,  Midori A Arai 1,  Takashi Koyano 2,  Thaworn Kowithayakorn 3,  Takamasa Mizoguchi 1,  Motoyuki Itoh 1,  Masami Ishibashi 1
Affiliations

Affiliations

  • 1 †Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
  • 2 ‡Temko Corporation, 4-27-4 Honcho, Nakano, Tokyo 164-0012, Japan.
  • 3 §Faculty of Agriculture, Khon Kaen University, Khon Kaen 40002, Thailand.
PMID: 25905468 DOI: 10.1021/acs.jnatprod.5b00153
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.

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