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

被引：34

作者：

Ohishi, Kensuke ^{[1
]}

Toume, Kazufumi ^{[1
]}

Arai, Midori A. ^{[1
]}

Koyano, Takashi ^{[2
]}

Kowithayakorn, Thaworn ^{[3
]}

Mizoguchi, Takamasa ^{[1
]}

Itoh, Motoyuki ^{[1
]}

Ishibashi, Masami ^{[1
]}

机构：

[1] Chiba Univ, Grad Sch Pharmaceut Sci, Chuo Ku, Chiba 2608675, Japan

[2] Temko Corp, Nakano Ku, Tokyo 1640012, Japan

[3] Khon Kaen Univ, Fac Agr, Khon Kaen 40002, Thailand

来源：

JOURNAL OF NATURAL PRODUCTS | 2015年 / 78卷 / 05期

关键词：

CATENIN; ZEBRAFISH; GROWTH; CELLS; LEF1; STEM;

D O I：

10.1021/acs.jnatprod.5b00153

中图分类号：

Q94 [植物学];

学科分类号：

071001 ;

摘要：

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/beta-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/beta-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 beta-catenin and increased phosphorylated beta-catenin (Ser 33, 37, Tyr 41) protein levels. The degradation of beta-catenin by 1 was suppressed by GSK3 beta-siRNA, while compound 1 decreased beta-catenin even in the presence of CK1 alpha-siRNA. These results suggest that 1 inhibits Wnt signaling through the activation of GSK3 beta independent of CK1 alpha.

引用

页码：1139 / 1146

页数：8