Niclosamide Suppresses Cancer Cell Growth By Inducing Wnt Co-Receptor LRP6 Degradation and Inhibiting the Wnt/β-Catenin Pathway

The Wnt/β-catenin signaling pathway is important for tumor initiation and progression. The low density lipoprotein receptor-related protein-6 (LRP6) is an essential Wnt co-receptor for Wnt/β-catenin signaling and represents a promising anticancer target. Recently, the antihelminthic drug, niclosamide was found to inhibit Wnt/β-catenin signaling, although the mechanism was not well defined. We found that niclosamide was able to suppress LRP6 expression and phosphorylation, block Wnt3A-induced β-catenin accumulation, and inhibit Wnt/β-catenin signaling in HEK293 cells. Furthermore, the inhibitory effects of niclosamide on LRP6 expression/phosphorylation and Wnt/β-catenin signaling were conformed in human prostate PC-3 and DU145 and breast MDA-MB-231 and T-47D cancer cells. Moreover, we showed that the mechanism by which niclosamide suppressed LRP6 resulted from increased degradation as evident by a shorter half-life. Finally, we demonstrated that niclosamide was able to induce cancer cell apoptosis, and displayed excellent anticancer activity with IC50 values less than 1 µM for prostate PC-3 and DU145 and breast MDA-MB-231 and T-47D cancer cells. The IC50 values are comparable to those shown to suppress the activities of Wnt/β-catenin signaling in prostate and breast cancer cells. Our data indicate that niclosamide is a unique small molecule Wnt/β-catenin signaling inhibitor targeting the Wnt co-receptor LRP6 on the cell surface, and that niclosamide has a potential to be developed a novel chemopreventive or therapeutic agent for human prostate and breast cancer

Atlanta or Fingal captured 1863 in Savannah

Broadside view of ironclad.Possibly by William Waud.Title inscribed below image.Gift, J.P. Morgan, 1919 (DLC/PP-1919:R1.2.541)Forms part of: Morgan collection of Civil War drawings

The rebel fleet of flag of truce boats in the Savannah River going down to the Leary & Hermann Livingstone to take off rebel prisoners

Title inscribed below image.Inscribed vertically above image: The Swan of Savannah; Fort Pulaski; Beauregard; The Ida; The Livingstone; The George Leary; The Genl Lee; Inscribed lower right: See New York Times.The Livingstone and The Georgy Leary are identified as Union ships.Possibly by William Waud.Gift, J.P. Morgan, 1919 (DLC/PP-1919:R1.2.765)Forms part of: Morgan collection of Civil War drawings

The place of exchange in the Savannah river looking toward the city, the rebel boat Beauregard coming down to meet the flag of truce

Drawing possibly by William Waud.Title inscribed on sheet affixed to verso.Inscribed above image with indicators: Savannah; Old duelling ground; Venus point.Gift, J.P. Morgan, 1919 (DLC/PP-1919:R2.2.457)Forms part of: Morgan collection of Civil War drawings

Battery Creighton. Jacksonville, Fa.

Title inscribed below image.Formerly Waud no. B-52.Possibly by William Waud.Gift, J.P. Morgan, 1919 (DLC/PP-1919:R2.2.817)Forms part of: Morgan collection of Civil War drawings

Columbia ashore Sullivans Island

Title inscribed upper left.Inscribed on hull of ship: cppr [ie. copper]Date derived from historical sources.Possibly by William Waud.Gift, J.P. Morgan, 1919 (DLC/PP-1919:R2.2.455 recto)Forms part of: Morgan collection of Civil War drawings

Key West, 1862

Details of fort with inset.Possibly by William Waud.Title inscribed upper right.Inscribed upper right: Cocoa. Inscribed below image inset: Ft. Taylor.Sketch of sailboat on verso (has been divided for recto sketch). Inscribed below image: Waterwitch-27.Formerly Waud no. C-96.Gift, J.P. Morgan, 1919 (DLC/PP-1919:R1.2.1023)Forms part of: Morgan collection of Civil War drawings

Bay Point Rebel Battery & camp on St Phillips Island north side of entrance to Broad River [Georgia] South Carolina

Title inscribed below image.Inscribed below title: You had better not use this sketch as I can get nearer probably.Inscribed within image as indicators: water; sand beach; thick woods; Rebel tug; Bank; Beach; high open trees; bank; beach.Possibly by William Waud.Gift, J.P. Morgan, 1919 (DLC/PP-1919:R1.2.1099 recto)Forms part of: Morgan collection of Civil War drawings

Lays Ferry. Oostanuala river. May 14-15-16 1864

Possibly by William Waud.Title inscribed upper right.Inscribed within image: Horn Mts. Chattougata Mts.Gift, J.P. Morgan, 1919 (DLC/PP-1919:R1.2.624)Forms part of: Morgan collection of Civil War drawings