Calotropin: A Cardenolide from Calotropis gigantea that Inhibits Wnt Signaling by Increasing Casein Kinase 1α in Colon Cancer Cells

被引：40

作者：

Park, Hyun Young ^{[1
]}

Toume, Kazufumi ^{[1
]}

Arai, Midori A. ^{[1
]}

Sadhu, Samir K. ^{[2
]}

Ahmed, Firoj ^{[3
]}

Ishibashi, Masami ^{[1
]}

机构：

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

[2] Khulna Univ, Sch Life Sci, Pharm Discipline, Khulna 9280, Bangladesh

[3] Univ Dhaka, Dept Pharmaceut Chem, Dhaka 1000, Bangladesh

来源：

CHEMBIOCHEM | 2014年 / 15卷 / 06期

基金：

日本学术振兴会;

关键词：

Calotropis gigantea; cardenolides; casein kinase 1alpha; natural products; signal transduction; Wnt signaling; BETA-CATENIN; PATHWAY; GROWTH; GLYCOSIDES; ACTIVATION; MUTATIONS; MECHANISM; CARCINOMA; DISEASE; PROCERA;

D O I：

10.1002/cbic.201300786

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Wnt signaling plays key roles in embryonic development and various human diseases. Activity-guided testing to isolate Wnt signaling inhibitors from the methanol extract of Calotropis gigantea (Asclepiadaceae) exudutes identified six Wnt inhibitory cardenolides (1-6), of which 1, 3, 5, and 6 exhibited potent TCF/-catenin inhibitory activities (IC50 0.7-3.6 nM). Calotropin (1) inhibited Wnt signaling by decreasing both nuclear and cytosolic -catenin in a dose-dependent manner, and promoted degradation of -catenin by increasing the phosphorylation of -catenin at Ser45 through casein kinase 1 (CK1). Moreover, 1 significantly increased CK1 protein and mRNA levels. The results suggest that 1 inhibits the Wnt signaling pathway by increasing CK1 protein levels. To the best of our knowledge, calotropin is the first small molecule to increase CK1 levels.

引用

页码：872 / 878

页数：7

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