Abstract
Aberrant activation of Wnt/β-catenin signaling and subsequent up-regulation of β-catenin response transcription (CRT) is a critical event in the development of human colon cancer. Thus, Wnt/β-catenin signaling is an attractive target for the development of anticancer therapeutics. In this study, we identified hexachlorophene as an inhibitor of Wnt/β-catenin signaling from cell-based small-molecule screening. Hexachlorophene antagonized CRT that was stimulated by Wnt3a-conditioned medium by promoting the degradation of β-catenin. This degradation pathway is Siah-1 and adenomatous polyposis colidependent, but glycogen synthase kinase-3β and F-box β-transducin repeat-containing protein-independent. In addition, hexachlorophene represses the expression of cyclin D1, which is a known β-catenin target gene, and inhibits the growth of colon cancer cells. Our findings suggest that hexachlorophene attenuates Wnt/β-catenin signaling through the Siah-1-mediated β-catenin degradation.
Footnotes
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This work was supported by Korea Research Foundation grant KRF-2004-041-400255 and a grant from Korea Health 21 R&D Project (03-PJ10-PG13-GD01-002).
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S.P. and J.G. contributed equally to this work.
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ABBREVIATIONS: CRT, β-catenin response transcription; APC, adenomatous polyposis coli; GSK-3β, glycogen synthase kinase-3β; Wnt3a CM, Wnt3a conditioned medium; β-TrCP, β-transducin repeat-containing protein; HEK, human embryonic kidney; hFz-1, human Frizzled-1; PCR, polymerase chain reaction; RT-PCR, reverse transcription-polymerase chain reaction; DMSO, dimethyl sulfoxide; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MG-132, N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal.
- Received March 20, 2006.
- Accepted May 25, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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