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Hexachlorophene Inhibits Wnt/-Catenin Pathway by Promoting Siah-Mediated -Catenin Degradation

PharmcoGenomics Research Center, Inje University, Busan, Korea (S.P., J.G., M.C., T.S., J.-G.S., S.O.); Department of Biological Science, Korea Advanced Institute of Science and Technology, Daejeon, Korea (J.W.); Department of Biotechnology & Bioengineering, Dong-Eui University, Busan, Korea (D.-E.K.); and Department of Pharmacology, Inje University College of Medicine, Busan, Korea (J.-G.S.)

Aberrant activation of Wnt/-catenin signaling and subsequent up-regulation of -catenin response transcription (CRT) is a critical event in the development of human colon cancer. Thus, Wnt/-catenin signaling is an attractive target for the development of anticancer therapeutics. In this study, we identified hexachlorophene as an inhibitor of Wnt/-catenin signaling from cell-based small-molecule screening. Hexachlorophene antagonized CRT that was stimulated by Wnt3a-conditioned medium by promoting the degradation of -catenin. This degradation pathway is Siah-1 and adenomatous polyposis colidependent, but glycogen synthase kinase-3 and F-box -transducin repeat-containing protein-independent. In addition, hexachlorophene represses the expression of cyclin D1, which is a known -catenin target gene, and inhibits the growth of colon cancer cells. Our findings suggest that hexachlorophene attenuates Wnt/-catenin signaling through the Siah-1-mediated -catenin degradation.

Address correspondence to: Dr. Sangtaek Oh, PharmcoGenomics Research Center, Inje University, Busan 614-735, Korea. E-mail: ohsa{at}inje.ac.kr

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