TY - JOUR
T1 - 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
AU - Ohishi, Kensuke
AU - Toume, Kazufumi
AU - Arai, Midori A.
AU - Koyano, Takashi
AU - Kowithayakorn, Thaworn
AU - Mizoguchi, Takamasa
AU - Itoh, Motoyuki
AU - Ishibashi, Masami
N1 - Publisher Copyright:
© 2015 The American Chemical Society and American Society of Pharmacognosy.
PY - 2015/5/22
Y1 - 2015/5/22
N2 - 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.
AB - 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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U2 - 10.1021/acs.jnatprod.5b00153
DO - 10.1021/acs.jnatprod.5b00153
M3 - Article
C2 - 25905468
AN - SCOPUS:84930216410
SN - 0163-3864
VL - 78
SP - 1139
EP - 1146
JO - Journal of Natural Products
JF - Journal of Natural Products
IS - 5
ER -