title: Calotropin: a cardenolide from calotropis gigantea that inhibits Wnt signaling by increasing casein kinase 1α in colon cancer cells.
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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675 (Japan).
authors.forename: Hyun Young
authors.initials: HY
authors.lastname: Park
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Toume
authors.forename: Midori A
authors.initials: MA
authors.lastname: Arai
authors.forename: Samir K
authors.initials: SK
authors.lastname: Sadhu
authors.forename: Firoj
authors.initials: F
authors.lastname: Ahmed
authors.forename: Masami
authors.initials: M
authors.lastname: Ishibashi
mesh_terms: D031107:Calotropis / Q000737:chemistry* / Q000378:metabolism; D002298:Cardenolides / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D048128:Casein Kinase Ialpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D002298:Cardenolides; D012333:RNA, Messenger; D051153:Wnt Proteins; D051176:beta Catenin; C546414:calotropin; D048128:Casein Kinase Ialpha
keywords: Calotropis gigantea; Wnt signaling; cardenolides; casein kinase 1alpha; natural products; signal transduction