TY - JOUR T1 - Berberine represses β-catenin translation involving 4E-BPs in hepatocellular carcinoma cells JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/molpharm.120.000029 SP - MOLPHARM-AR-2020-000029 AU - Kanchan Vishnoi AU - Rong Ke AU - Karan S Saini AU - Navin Viswakarma AU - Rakesh Sathish Nair AU - Subhasis Das AU - Zhengjia Chen AU - Ajay Rana AU - Basabi Rana Y1 - 2020/01/01 UR - http://molpharm.aspetjournals.org/content/early/2020/10/31/molpharm.120.000029.abstract N2 - Aberrant activation of Wnt/β-catenin axis occurs in several gastrointestinal malignancies due to inactivating mutations of APC (in colorectal cancer) or activating mutations of β-catenin itself (in hepatocellular carcinoma [HCC]). These lead to β-catenin stabilization, increase in β-catenin/TCF-mediated transcriptional activation and target gene expression, many of which are involved in tumor progression. While studying pharmaceutical agents that can target β-catenin in cancer cells, we observed that the plant compound berberine (BBR), a potent activator of AMP-activated protein kinase (AMPK), can reduce β-catenin expression and downstream signaling in HCC cells in a dose dependent manner. More in depth analyses to understand the mechanism revealed that BBR-induced reduction of β-catenin occurs independently of AMPK activation, and does-not involve transcriptional or post-translational mechanisms. Pretreatment with protein synthesis inhibitor Cycloheximide antagonized BBR-induced β-catenin reduction, suggesting that BBR affects β-catenin translation. BBR treatment also antagonized mTOR activity, and was associated with increased recruitment of eIF4E-binding protein 1 (4E-BP1) in the translational complex, as revealed by m7-cap-binding assays, suggesting inhibition of cap-dependent translation. Interestingly, knocking down 4E-BP1 and -2 significantly attenuated BBR-induced reduction of β-catenin levels and expression of its downstream target genes. Moreover, cells with 4E-BP knockdown were resistant to BBR-induced cell death, and were re-sensitized to BBR following pharmacological inhibition of β-catenin. Our findings indicate that BBR antagonizes β-catenin pathway by inhibiting β-catenin translation and mTOR activity and thereby reduces HCC cell survival. These also suggest that BBR could be utilized for targeting HCCs that express mutated/activated β-catenin variants that are currently undruggable. Significance Statement β-catenin signaling is aberrantly activated in different gastrointestinal cancers, including HCC, which is currently undruggable. In this study we describe a novel mechanism of targeting β-catenin translation via utilizing a plant compound BBR. Our findings provide a new avenue of targeting β-catenin axis in cancer, which can be utilized towards the designing of effective therapeutic strategies to combat β-catenin-dependent cancers. ER -