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First published on May 30, 2006; DOI: 10.1124/mol.106.024729

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Received for publication March 21, 2006.
Revised May 22, 2006.
Accepted for publication May 25, 2006.

Hexachlorophene inhibits Wnt/{beta}-catenin pathway by promoting Siah-mediated {beta}-catenin degradation

Seoyoung Park 1, Jungsug Gwak 1, Munju Cho 1, Taeyun Song 1, Jaejoon Won 2, Dong-Eun Kim 3, Jae-Gook Shin 1, Sangtaek Oh 1*

1 Inje University 2 KAIST 3 Dong-Eui University

* Address correspondence to: E-mail: ohsa{at}inje.ac.kr

Abstract

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


Key words: Oncogenes, Transcription targets, Tumor suppressors


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