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

Kensuke Ohishi, Kazufumi Toume, Midori A. Arai, Takashi Koyano, Thaworn Kowithayakorn, Takamasa Mizoguchi, Motoyuki Itoh, Masami Ishibashi

研究成果: Article査読

30 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)1139-1146
ページ数8
ジャーナルJournal of Natural Products
78
5
DOI
出版ステータスPublished - 2015 5 22
外部発表はい

ASJC Scopus subject areas

  • 分析化学
  • 分子医療
  • 薬理学
  • 薬科学
  • 創薬
  • 補完代替医療
  • 有機化学

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