Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α.
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.
Thorne
Curtis A
CA
Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Hanson
Alison J
AJ
Schneider
Judsen
J
Tahinci
Emilios
E
Orton
Darren
D
Cselenyi
Christopher S
CS
Jernigan
Kristin K
KK
Meyers
Kelly C
KC
Hang
Brian I
BI
Waterson
Alex G
AG
Kim
Kwangho
K
Melancon
Bruce
B
Ghidu
Victor P
VP
Sulikowski
Gary A
GA
LaFleur
Bonnie
B
Salic
Adrian
A
Lee
Laura A
LA
Miller
David M
DM
Lee
Ethan
E
D048868:Adaptor Proteins, Signal Transducing; D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism; D000818:Animals; D060466:Axin Protein; D047389:Casein Kinase I / Q000235:genetics / Q000378:metabolism; D048128:Casein Kinase Ialpha / Q000378:metabolism*; D002457:Cell Extracts; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D011774:Pyrvinium Compounds / Q000494:pharmacology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D029867:Xenopus Proteins; D014982:Xenopus laevis; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D060466:Axin Protein; D002457:Cell Extracts; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; C453402:PYGO1 protein, human; D011774:Pyrvinium Compounds; D012097:Repressor Proteins; D051153:Wnt Proteins; D029867:Xenopus Proteins; C555454:axin1 protein, Xenopus; D051176:beta Catenin; C024631:pyrvinium; D047389:Casein Kinase I; D048128:Casein Kinase Ialpha