Cytotoxic activity of broussochalcone a against colon and liver cancer cells by promoting destruction complex-independent beta-catenin degradation

Abstract

Aberrant activation of beta-catenin-response transcription (CRT) is a well-recognized characteristic of olorectal and liver cancers and thus a potential therapeutic target for these malignancies. Broussonetia papyrifera (paper mulberry) has been used as a herbal medicine to treat various diseases. Using a sensitive cell-based screening system, we identified broussochalcone A (BCA), a prenylated chalcone isolated from Broussonetia papyrifera, as an antagonist of CRT. BCA accelerated the turnover of intracellular beta-catenin that was accompanied by its N-terminal phosphorylation at Ser33/37/Thr41 residues, marking it for ubiquitin-dependent proteasomal degradation. Pharmacological inhibition of glycogen synthase kinase-3 beta could not abrogate BCA-mediated degradation of beta-catenin. BCA decreased the intracellular beta-catenin levels in colon and liver cancer cells with mutations in beta-catenin, adenomatous polyposis coli, and Axin. BCA repressed the expressions of cyclin D1, c-Myc, and Axing, which are beta-catenin/T-cell factor-dependent genes, and thus decreased the viability of colon and liver cancer cell. Moreover, apoptosis was elicited by BCA, as indicated by the increase in the population of Annexin V-FITC positive cells and caspase-3/7 activities in colon and liver cancer cells. These findings indicate that BCA exerts its cytotoxic effects by promoting phosphorylation/ubiquitin-dependent degradation of beta-catenin and may potentially serve as a chemopreventive agent for colonrectal and liver cancers.