Berberine Inhibits Growth of Liver Cancer Cells by Suppressing Glutamine Uptake

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.