Z-Ajoene Inhibits Growth of Colon Cancer by Promotion of CK1 alpha Dependent beta-Catenin Phosphorylation

Abstract

Aberrant activation of a Wnt/beta-catenin pathway results in nuclear accumulation of beta-catenin in colon cancer. Inhibiting beta-catenin is one strategy for treating colon cancer. Here, we identified Z-ajoene, a sulfur containing compound isolated from crushed garlic, as an inhibitor of colon cancer cell growth. Z-Ajoene repressed beta-catenin response transcriptional activity, intracellular beta-catenin levels, and its representative target protein levels (c-Myc and cyclin D1) in SW480 colon cancer cells. To clarify the regulatory mechanism of decreased beta-catenin levels, we examined the effect of Z-ajoene on beta-catenin phosphorylation, which is involved in beta-catenin degradation. Z-Ajoene promoted the phosphorylation of beta-catenin at Ser45 in a casein kinase 1 alpha (CK1 alpha)-dependent manner, which is an essential step in beta-catenin degradation in the cytosol. These findings indicate that Z-ajoene from garlic may be a potential chemotherapeutic agent by modulating CK1 alpha activity and the Wnt/beta-catenin signaling pathway.