Inhibition of β-catenin-mediated transactivation by flavanone in AGS gastric cancer cells

Recently, data which prove that Writ pathway activation may be an early event in multistep carcinogenesis in the stomach have been accumulating. We examined the effect of flavanone against beta-catenin/Tef signaling in AGS gastric cancer cells. Reporter gene assay showed that flavanone inhibited beta-catenin/Tcf signaling efficiently. In addition, the inhibition of beta-catenin/Tcf signaling by flavanone in HEK293 cells transiently transfected with constitutively mutant beta-catenin gene, whose product is not phosphorylated by GSK3 beta, indicates that its inhibitory mechanism was related to beta-catenin itself or downstream components. To investigate the precise inhibitory mechanism, we performed immunofluorescence, Western blot, and EMSA. As a result, our data revealed that there is no change of beta-catenin distribution and of nuclear beta-catenin levels through flavanone. In addition, the binding of Tcf complexes to DNA is not influenced by flavanone. The beta-catenin/Tcf transcriptional target gene cyclinD1 was downregulated by flavanone. These data suggest that flavanone inhibits the transcription of beta-catenin/Tcf responsive genes, by modulating Tcf activity without disrupting beta-catenin/Tcf complex formation. (c) 2005 Elsevier Inc. All rights reserved.