Park Seoyoung, Gwak Jungsug, Cho Munju, Song Taeyun, Won Jaejoon, Kim Dong-Eun, Shin Jae-Gook, Oh Sangtaek
PharmcoGenomics Research Center, Inje University, Busan 614-735, Korea.
Mol Pharmacol. 2006 Sep;70(3):960-6. doi: 10.1124/mol.106.024729. Epub 2006 May 30.
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.
Wnt/β-连环蛋白信号通路的异常激活以及随后β-连环蛋白反应转录（CRT）的上调是人类结肠癌发生发展中的关键事件。因此，Wnt/β-连环蛋白信号通路是开发抗癌治疗药物的一个有吸引力的靶点。在本研究中，我们通过基于细胞的小分子筛选鉴定出六氯酚是Wnt/β-连环蛋白信号通路的抑制剂。六氯酚通过促进β-连环蛋白的降解来拮抗由Wnt3a条件培养基刺激的CRT。这种降解途径依赖于Siah-1和腺瘤性息肉病结肠，但不依赖糖原合酶激酶-3β和含F-boxβ-转导蛋白重复序列的蛋白。此外，六氯酚可抑制细胞周期蛋白D1的表达，细胞周期蛋白D1是一种已知的β-连环蛋白靶基因，并抑制结肠癌细胞的生长。我们的研究结果表明，六氯酚通过Siah-1介导的β-连环蛋白降解来减弱Wnt/β-连环蛋白信号通路。
