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

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-1mediated -catenin degradation. Wnts are secreted glycoproteins that play important roles in cell proliferation, differentiation, and oncogenesis (Peifer and Polakis, 2000; Huelsken and Birchmeier, 2001). Central to this pathway is the level of cytosolic -catenin, which regulates its target genes. The level of -catenin is regulated by two adenomatous polyposis coli (APC)-dependent proteasomal degradation pathways, a glycogen synthase kinase-3 (GSK-3 )-dependent pathway (Polakis, 2002), and an Siah1-dependent pathway (Liu et al., 2001). In the GSK-3 -dependent pathway, -catenin is phosphorylated by a multiprotein complex composed of APC, Axin, and GSK-3 (Hart et al., 1998; Ikeda et al., 1998), leading to the degradation of -catenin through a ubiquitin-dependent mechanism (Aberle et al., 1997). In the Siah-1-dependent pathway, Siah-1 interacts with the carboxyl terminus of APC, recruits the ubiquitination complex, and promotes the degradation of -catenin through a pathway independent of both GSK-3 and -TrCP, an F-box protein in the E3 ubiquitin ligase complex