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Research ArticleArticle

Berberine Represses β-Catenin Translation Involving 4E-BPs in Hepatocellular Carcinoma Cells

Kanchan Vishnoi, Rong Ke, Karan S. Saini, Navin Viswakarma, Rakesh Sathish Nair, Subhasis Das, Zhengjia Chen, Ajay Rana and Basabi Rana
Molecular Pharmacology January 2021, 99 (1) 1-16; DOI: https://doi.org/10.1124/molpharm.120.000029
Kanchan Vishnoi
Department of Surgery, Division of Surgical Oncology (K.V., R.K., K.S.S., N.V., R.S.N., S.D., A.R., B.R.), University of Illinois Hospital and Health Sciences System Cancer Center (S.D., A.R., B.R.), and Division of Epidemiology and Biostatistics, School of Public Health (Z.C.), University of Illinois at Chicago, Chicago, Illinois; Biostatistics Shared Resource Core, University of Illinois Cancer Institute, Chicago, Illinois (Z.C.); and Jesse Brown VA Medical Center, Chicago, Illinois (A.R., B.R.)
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Rong Ke
Department of Surgery, Division of Surgical Oncology (K.V., R.K., K.S.S., N.V., R.S.N., S.D., A.R., B.R.), University of Illinois Hospital and Health Sciences System Cancer Center (S.D., A.R., B.R.), and Division of Epidemiology and Biostatistics, School of Public Health (Z.C.), University of Illinois at Chicago, Chicago, Illinois; Biostatistics Shared Resource Core, University of Illinois Cancer Institute, Chicago, Illinois (Z.C.); and Jesse Brown VA Medical Center, Chicago, Illinois (A.R., B.R.)
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Karan S. Saini
Department of Surgery, Division of Surgical Oncology (K.V., R.K., K.S.S., N.V., R.S.N., S.D., A.R., B.R.), University of Illinois Hospital and Health Sciences System Cancer Center (S.D., A.R., B.R.), and Division of Epidemiology and Biostatistics, School of Public Health (Z.C.), University of Illinois at Chicago, Chicago, Illinois; Biostatistics Shared Resource Core, University of Illinois Cancer Institute, Chicago, Illinois (Z.C.); and Jesse Brown VA Medical Center, Chicago, Illinois (A.R., B.R.)
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Navin Viswakarma
Department of Surgery, Division of Surgical Oncology (K.V., R.K., K.S.S., N.V., R.S.N., S.D., A.R., B.R.), University of Illinois Hospital and Health Sciences System Cancer Center (S.D., A.R., B.R.), and Division of Epidemiology and Biostatistics, School of Public Health (Z.C.), University of Illinois at Chicago, Chicago, Illinois; Biostatistics Shared Resource Core, University of Illinois Cancer Institute, Chicago, Illinois (Z.C.); and Jesse Brown VA Medical Center, Chicago, Illinois (A.R., B.R.)
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Rakesh Sathish Nair
Department of Surgery, Division of Surgical Oncology (K.V., R.K., K.S.S., N.V., R.S.N., S.D., A.R., B.R.), University of Illinois Hospital and Health Sciences System Cancer Center (S.D., A.R., B.R.), and Division of Epidemiology and Biostatistics, School of Public Health (Z.C.), University of Illinois at Chicago, Chicago, Illinois; Biostatistics Shared Resource Core, University of Illinois Cancer Institute, Chicago, Illinois (Z.C.); and Jesse Brown VA Medical Center, Chicago, Illinois (A.R., B.R.)
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Subhasis Das
Department of Surgery, Division of Surgical Oncology (K.V., R.K., K.S.S., N.V., R.S.N., S.D., A.R., B.R.), University of Illinois Hospital and Health Sciences System Cancer Center (S.D., A.R., B.R.), and Division of Epidemiology and Biostatistics, School of Public Health (Z.C.), University of Illinois at Chicago, Chicago, Illinois; Biostatistics Shared Resource Core, University of Illinois Cancer Institute, Chicago, Illinois (Z.C.); and Jesse Brown VA Medical Center, Chicago, Illinois (A.R., B.R.)
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Zhengjia Chen
Department of Surgery, Division of Surgical Oncology (K.V., R.K., K.S.S., N.V., R.S.N., S.D., A.R., B.R.), University of Illinois Hospital and Health Sciences System Cancer Center (S.D., A.R., B.R.), and Division of Epidemiology and Biostatistics, School of Public Health (Z.C.), University of Illinois at Chicago, Chicago, Illinois; Biostatistics Shared Resource Core, University of Illinois Cancer Institute, Chicago, Illinois (Z.C.); and Jesse Brown VA Medical Center, Chicago, Illinois (A.R., B.R.)
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Ajay Rana
Department of Surgery, Division of Surgical Oncology (K.V., R.K., K.S.S., N.V., R.S.N., S.D., A.R., B.R.), University of Illinois Hospital and Health Sciences System Cancer Center (S.D., A.R., B.R.), and Division of Epidemiology and Biostatistics, School of Public Health (Z.C.), University of Illinois at Chicago, Chicago, Illinois; Biostatistics Shared Resource Core, University of Illinois Cancer Institute, Chicago, Illinois (Z.C.); and Jesse Brown VA Medical Center, Chicago, Illinois (A.R., B.R.)
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Basabi Rana
Department of Surgery, Division of Surgical Oncology (K.V., R.K., K.S.S., N.V., R.S.N., S.D., A.R., B.R.), University of Illinois Hospital and Health Sciences System Cancer Center (S.D., A.R., B.R.), and Division of Epidemiology and Biostatistics, School of Public Health (Z.C.), University of Illinois at Chicago, Chicago, Illinois; Biostatistics Shared Resource Core, University of Illinois Cancer Institute, Chicago, Illinois (Z.C.); and Jesse Brown VA Medical Center, Chicago, Illinois (A.R., B.R.)
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Abstract

Aberrant activation of Wnt/β-catenin axis occurs in several gastrointestinal malignancies due to inactivating mutations of adenomatous polyposis coli (in colorectal cancer) or activating mutations of β-catenin itself [in hepatocellular carcinoma (HCC)]. These lead to β-catenin stabilization, increase in β-catenin/T-cell factor (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 mammalian target of rapamycin (mTOR) activity and was associated with increased recruitment of eukaryotic translation initiation factor 4E–binding protein (4E-BP) 1 in the translational complex, which was revealed by 7-methyl-cap–binding assays, suggesting inhibition of cap-dependent translation. Interestingly, knocking down 4E-BP1 and 4E-BP2 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 resensitized to BBR after 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 used 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 hepatocellular carcinoma, which is currently undruggable. In this study we describe a novel mechanism of targeting β-catenin translation via utilizing a plant compound, berberine. Our findings provide a new avenue of targeting β-catenin axis in cancer, which can be utilized toward the designing of effective therapeutic strategies to combat β-catenin–dependent cancers.

Footnotes

    • Received April 2, 2020.
    • Accepted October 2, 2020.
  • ↵1 K.V. and R.K. contributed equally to this work.

  • This work was supported by National Institutes of Health National Cancer Institute [Grants R01 CA178063 and R03 CA219764] (to B.R.) and [Grants R01 CA176846 and R01 CA216410] (to A.R.) as well as the Veterans Affairs Merit Award [Grant I01 BX003296] (to B.R.) and [Grants I01 BX002703 and I01 BX002355] (to A.R).

  • https://doi.org/10.1124/molpharm.120.000029.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 99 (1)
Molecular Pharmacology
Vol. 99, Issue 1
1 Jan 2021
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Research ArticleArticle

Berberine Represses β-Catenin Translation

Kanchan Vishnoi, Rong Ke, Karan S. Saini, Navin Viswakarma, Rakesh Sathish Nair, Subhasis Das, Zhengjia Chen, Ajay Rana and Basabi Rana
Molecular Pharmacology January 1, 2021, 99 (1) 1-16; DOI: https://doi.org/10.1124/molpharm.120.000029

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Research ArticleArticle

Berberine Represses β-Catenin Translation

Kanchan Vishnoi, Rong Ke, Karan S. Saini, Navin Viswakarma, Rakesh Sathish Nair, Subhasis Das, Zhengjia Chen, Ajay Rana and Basabi Rana
Molecular Pharmacology January 1, 2021, 99 (1) 1-16; DOI: https://doi.org/10.1124/molpharm.120.000029
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