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

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Abstract
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/β-catenin inhibitory activities (IC50 0.7–3.6 nM). Calotropin (1) inhibited Wnt signaling by decreasing both nuclear and cytosolic β-catenin in a dose-dependent manner, and promoted degradation of β-catenin by increasing the phosphorylation of β-catenin at Ser45 through casein kinase 1α (CK1α). Moreover, 1 significantly increased CK1α protein and mRNA levels. The results suggest that 1 inhibits the Wnt signaling pathway by increasing CK1α protein levels. To the best of our knowledge, calotropin is the first small molecule to increase CK1α levels.

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