Galangin is a naturally occurring bioflavonoid with anticancer activity against certain human cancers, yet little is known about its mechanism of action. Here, we used a chemical biology approach to reveal that galangin suppresses -catenin response transcription (CRT), which is aberrantly up-regulated in colorectal and liver cancers, by promoting the degradation of intracellular -catenin. Inhibition of glycogen synthase kinase-3 (GSK-3) activity or mutation of the GSK-3-targeted sequence from -catenin was unable to abrogate the galanginmediated degradation of -catenin. In addition, galangin downregulated the intracellular -catenin levels in cancer cells with inactivating mutations of adenomatous polyposis coli (APC) or Axin, which are components of the -catenin destruction complex. Galangin repressed the expression of -catenin/T-cell factor-dependent genes, such as cyclin D1 and c-myc, and thus inhibited the proliferation of CRT-positive cancer cells. Structure-activity data indicated that the major structural requirements for galangin-mediated -catenin degradation are hydroxyl groups at positions 3, 5, and 7. Our findings suggest that galangin exerts its anticancer activity by promoting APC/Axin/GSK-3-independent proteasomal degradation of -catenin.
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