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      OncoTargets and Therapy (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the pathological basis of cancers, potential targets for therapy and treatment protocols to improve the management of cancer patients. Publishing high-quality, original research on molecular aspects of cancer, including the molecular diagnosis, since 2008. Sign up for email alerts here. 50,877 Monthly downloads/views I 4.345 Impact Factor I 7.0 CiteScore I 0.81 Source Normalized Impact per Paper (SNIP) I 0.811 Scimago Journal & Country Rank (SJR)

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      Berberine Inhibits Growth of Liver Cancer Cells by Suppressing Glutamine Uptake

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          Abstract

          Introduction

          Glutamine metabolism is essential for the proliferation of cancer cells. Transported by SLC1A5, a Na + dependent transporter, glutamine is absorbed for further use. Recent studies have revealed the anti-tumor effect of berberine. The present study aimed to evaluate the effect of berberine on cancer cell glutamine metabolism.

          Materials and methods

          The inhibitory effect of berberine on liver cancer cells was analyzed by CCK-8 and EdU assay. The glutamine concentrations were detected by ELISA and UHPLC-MRM-MS analysis. Glutamine metabolism-related proteins were determined by Western blot, immunofluorescent analysis and immunohistochemistry.

          Results

          Berberine inhibited the proliferation of Hep3B and BEL-7404 cell in vitro. Berberine suppressed the glutamine uptake by inhibiting SLC1A5. The upregulation of SLC1A5 led to an increased glutamine uptake and improved tolerance to berberine. Berberine suppresses SLC1A5 expression by inhibiting c-Myc. Furthermore, berberine suppresses the growth of tumor xenografts, and the expression of SLC1A5 and c-Myc in vivo. The high expression of SLC1A5 in hepatocellular carcinoma (HCC) tissues is associated with poor prognosis.

          Conclusion

          Berberine can suppress the proliferation of liver cancer cells by reducing SLC1A5 expression.

          Most cited references18

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          The metabolism of berberine and its contribution to the pharmacological effects.

          Kun Wang, Xinchi Feng, Liwei Chai … (2017)
          Berberine, a bioactive alkaloid isolated from several herbal substances, possesses multiple pharmacological effects, including antimicrobial, antidiabetic, anticancer activities. Meanwhile, berberine undergoes extensive metabolism after oral administration which results in its extremely low plasma exposure. Therefore, it is believed that the metabolites of berberine also contribute a lot to its pharmacological effects. Along these lines, this review covers the metabolism studies of berberine in terms of its metabolic pathways and metabolic organs based on the identified metabolites, and it also covers the pharmacological activities of its active metabolites. In brief, the predominant metabolic pathways of berberine are demethylation, demethylenation, reduction, hydroxylation and subsequent conjugation in vivo. Active metabolites such as columbamine, berberrubine and demethyleneberberine also exhibit similar pharmacological effects by comparison with berberine, such as antioxidant, anti-inflammatory, antitumor, antimicrobial, hepatoprotective, neuroprotective, hypolipidemic and hypoglycemic effects. Overall, berberine together with its metabolites formed the material basis of berberine in vivo.
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            Targeting glutamine transport to suppress melanoma cell growth.

            Kimberley A. Beaumont, Nicholas J Otte, Josep Font … (2014)
            Amino acids, especially leucine and glutamine, are important for tumor cell growth, survival and metabolism. A range of different transporters deliver each specific amino acid into cells, some of which are increased in cancer. These amino acids consequently activate the mTORC1 pathway and drive cell cycle progression. The leucine transporter LAT1/4F2hc heterodimer assembles as part of a large complex with the glutamine transporter ASCT2 to transport amino acids. In this study, we show that the expression of LAT1 and ASCT2 is significantly increased in human melanoma samples and is present in both BRAF(WT) (C8161 and WM852) and BRAF(V600E) mutant (1205Lu and 451Lu) melanoma cell lines. While inhibition of LAT1 by BCH did not suppress melanoma cell growth, the ASCT2 inhibitor BenSer significantly reduced both leucine and glutamine transport in melanoma cells, leading to inhibition of mTORC1 signaling. Cell proliferation and cell cycle progression were significantly reduced in the presence of BenSer in melanoma cells in 2D and 3D cell culture. This included reduced expression of the cell cycle regulators CDK1 and UBE2C. The importance of ASCT2 expression in melanoma was confirmed by shRNA knockdown, which inhibited glutamine uptake, mTORC1 signaling and cell proliferation. Taken together, our study demonstrates that ASCT2-mediated glutamine transport is a potential therapeutic target for both BRAF(WT) and BRAF(V600E) melanoma. © 2014 UICC.
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              The Human SLC1A5 (ASCT2) Amino Acid Transporter: From Function to Structure and Role in Cell Biology

              Mariafrancesca Scalise, Lorena Pochini, Lara Console … (2018)
              SLC1A5, known as ASCT2, is a neutral amino acid transporter belonging to the SLC1 family and localized in the plasma membrane of several body districts. ASCT2 is an acronym standing for Alanine, Serine, Cysteine Transporter 2 even if the preferred substrate is the conditionally essential amino acid glutamine, with cysteine being a modulator and not a substrate. The studies around amino acid transport in cells and tissues began in the ‘60s by using radiolabeled compounds and competition assays. After identification of murine and human genes, the function of the coded protein has been studied in cell system and in proteoliposomes revealing that this transporter is a Na+ dependent antiporter of neutral amino acids, some of which are only inwardly transported and others are bi-directionally exchanged. The functional asymmetry merged with the kinetic asymmetry in line with the physiological role of amino acid pool harmonization. An intriguing function has been described for ASCT2 that is exploited as a receptor by a group of retroviruses to infect human cells. Interactions with scaffold proteins and post-translational modifications regulate ASCT2 stability, trafficking and transport activity. Two asparagine residues, namely N163 and N212, are the sites of glycosylation that is responsible for the definitive localization into the plasma membrane. ASCT2 expression increases in highly proliferative cells such as inflammatory and stem cells to fulfill the augmented glutamine demand. Interestingly, for the same reason, the expression of ASCT2 is greatly enhanced in many human cancers. This finding has generated interest in its candidacy as a pharmacological target for new anticancer drugs. The recently solved 3D structure of ASCT2 will aid in the rational design of such therapeutic compounds.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Onco Targets Ther
                Journal ID (iso-abbrev): Onco Targets Ther
                Journal ID (publisher-id): OTT
                Journal ID (pmc): ott
                Title: OncoTargets and therapy
                Publisher: Dove
                ISSN (Electronic): 1178-6930
                Publication date (Electronic): 31 December 2019
                Publication date Collection: 2019
                Volume: 12
                Pages: 11751-11763
                Affiliations
                [1 ]Department of Hepato-Biliary and Pancreto-Splenic Surgery, Xijing Hospital, The Fourth Military Medical University , Xi’an, People’s Republic of China
                Author notes
                Correspondence: Ruohan Zhang; Kefeng Dou Department of Hepato-Biliary and Pancreto-Splenic Surgery, Xijing Hospital, The Fourth Military Medical University , No. 169 West Changle Road, Xi’an710000, People’s Republic of ChinaTel +86 150 2909 8264; +86 135 7189 0758 Email zhangrh1990@outlook.com; doukef@fmmu.edu.cn
                Author information
                http://orcid.org/0000-0002-9571-676X
                http://orcid.org/0000-0001-5138-3003
                Article
                Publisher ID: 235667
                DOI: 10.2147/OTT.S235667
                PMC ID: 6978679
                PubMed ID: 32021249
                SO-VID: 633141e2-0f2d-403d-8f8c-41c2dbe1ab94
                Copyright © © 2019 Zhang et al.
                License:

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                Date received : 22 October 2019
                Date accepted : 16 December 2019
                Page count
                Figures: 6, References: 37, Pages: 13
                Categories
                Subject: Original Research

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: berberine,hepatocellular carcinoma,slc1a5,glutamine metabolism
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: berberine, hepatocellular carcinoma, slc1a5, glutamine metabolism

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