Galangin Suppresses the Proliferation of β-Catenin Response Transcription-Positive Cancer Cells by Promoting Adenomatous Polyposis Coli/Axin/Glycogen Synthase Kinase-3β-Independent β-Catenin Degradation

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 beta-catenin response transcription (CRT), which is aberrantly up-regulated in colorectal and liver cancers, by promoting the degradation of intracellular beta-catenin. Inhibition of glycogen synthase kinase-3 beta (GSK-3 beta) activity or mutation of the GSK-3 beta-targeted sequence from beta-catenin was unable to abrogate the galangin-mediated degradation of beta-catenin. In addition, galangin downregulated the intracellular beta-catenin levels in cancer cells with inactivating mutations of adenomatous polyposis coli (APC) or Axin, which are components of the beta-catenin destruction complex. Galangin repressed the expression of beta-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 beta-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 beta-independent proteasomal degradation of beta-catenin.