Hexachlorophene inhibits Wnt/beta-catenin pathway by promoting Siah-mediated beta-catenin degradation.
Aberrant activation of Wnt/beta-catenin signaling and subsequent up-regulation of beta-catenin response transcription (CRT) is a critical event in the development of human colon cancer. Thus, Wnt/beta-catenin signaling is an attractive target for the development of anticancer therapeutics. In this study, we identified hexachlorophene as an inhibitor of Wnt/beta-catenin signaling from cell-based small-molecule screening. Hexachlorophene antagonized CRT that was stimulated by Wnt3a-conditioned medium by promoting the degradation of beta-catenin. This degradation pathway is Siah-1 and adenomatous polyposis colidependent, but glycogen synthase kinase-3beta and F-box beta-transducin repeat-containing protein-independent. In addition, hexachlorophene represses the expression of cyclin D1, which is a known beta-catenin target gene, and inhibits the growth of colon cancer cells. Our findings suggest that hexachlorophene attenuates Wnt/beta-catenin signaling through the Siah-1-mediated beta-catenin degradation.
Park
Seoyoung
S
PharmcoGenomics Research Center, Inje University, Busan 614-735, Korea.
Gwak
Jungsug
J
Cho
Munju
M
Song
Taeyun
T
Won
Jaejoon
J
Kim
Dong-Eun
DE
Shin
Jae-Gook
JG
Oh
Sangtaek
S
D000891:Anti-Infective Agents, Local / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006582:Hexachlorophene / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism; D000098563:Seven in Absentia Proteins
D000891:Anti-Infective Agents, Local; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D006582:Hexachlorophene