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Pyrvinium, a Potent Small Molecule Wnt Inhibitor, Promotes Wound Repair and Post-MI Cardiac Remodeling

Figure 1

Pyrvinium inhibits Wnt signaling.

(A) Pyrvinium inhibits TOPflash activation with an EC50 of ∼10 nM in contrast to the structurally related compound VU-WS211. HEK 293 STF (TOPflash) luciferase reporter cells incubated with Wnt3a-conditioned media were treated as indicated. Graph represents mean ± SEM of TOPflash signal normalized to cell number (performed in quadruplicate). (B) Pyrvinium (100 nM) decreases transcript levels of endogenous Wnt target genes Myc, Dkk-1, and Axin2 as assessed by real-time PCR. GAPDH is control. (C) Pyrvinium binds CK1α in vitro. CK1α and GSK3 (0.5 µg each, in duplicates) were spotted on nitrocellulose, incubated with pyrvinium (10 nM), and bound pyrvinium detected based on its fluorescent property. (D) Pyrvinium stimulates CK1α activity. CK1α (100 nM) was incubated with recombinant casein (100 nM) plus or minus pyrvinium (10 nM) in a kinase reaction containing [γ32P]ATP followed by SDS-PAGE and exposure to PhosphoImager screen. (E) Pyrvinium decreases and increases intracellular β-catenin and Axin levels, respectively. HEK 293 cells were treated for 16 hours as indicated, and cytoplasmic preparations were immunoblotted for β-catenin and Axin. β-tubulin is loading control. (F) Pyrvinium decrease steady-state levels of Pygopus. HEK 293 STF cells expressing HA-tagged human Pygopus-2 were treated with pyrvinium as indicated. Lysates were immunoblotted for HA. β-galactosidase (β-gal) is transfection control.

Figure 1

doi: https://doi.org/10.1371/journal.pone.0015521.g001