1. Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α.
- Author
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Thorne CA, Hanson AJ, Schneider J, Tahinci E, Orton D, Cselenyi CS, Jernigan KK, Meyers KC, Hang BI, Waterson AG, Kim K, Melancon B, Ghidu VP, Sulikowski GA, LaFleur B, Salic A, Lee LA, Miller DM 3rd, and Lee E
- Subjects
- Adaptor Proteins, Signal Transducing, Adenomatous Polyposis Coli genetics, Adenomatous Polyposis Coli metabolism, Animals, Axin Protein, Casein Kinase I genetics, Casein Kinase I metabolism, Cell Extracts, Cell Line, Tumor, Colonic Neoplasms metabolism, Colonic Neoplasms pathology, Dose-Response Relationship, Drug, Enzyme Activation drug effects, Humans, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Oocytes cytology, Oocytes metabolism, Repressor Proteins genetics, Repressor Proteins metabolism, Wnt Proteins chemistry, Wnt Proteins genetics, Wnt Proteins metabolism, Xenopus Proteins, Xenopus laevis, beta Catenin genetics, beta Catenin metabolism, Casein Kinase Ialpha metabolism, Cell Proliferation drug effects, Enzyme Inhibitors pharmacology, Pyrvinium Compounds pharmacology, Signal Transduction drug effects, Wnt Proteins antagonists & inhibitors
- Abstract
Wnt/β-catenin signaling is critically involved in metazoan development, stem cell maintenance and human disease. Using Xenopus laevis egg extract to screen for compounds that both stabilize Axin and promote β-catenin turnover, we identified an FDA-approved drug, pyrvinium, as a potent inhibitor of Wnt signaling (EC(50) of ∼10 nM). We show pyrvinium binds all casein kinase 1 (CK1) family members in vitro at low nanomolar concentrations and pyrvinium selectively potentiates casein kinase 1α (CK1α) kinase activity. CK1α knockdown abrogates the effects of pyrvinium on the Wnt pathway. In addition to its effects on Axin and β-catenin levels, pyrvinium promotes degradation of Pygopus, a Wnt transcriptional component. Pyrvinium treatment of colon cancer cells with mutation of the gene for adenomatous polyposis coli (APC) or β-catenin inhibits both Wnt signaling and proliferation. Our findings reveal allosteric activation of CK1α as an effective mechanism to inhibit Wnt signaling and highlight a new strategy for targeted therapeutics directed against the Wnt pathway.
- Published
- 2010
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