Berberine Inhibits Cell Proliferation by Interfering with Wild-Type and Mutant P53 in Human Glioma Cells

INTRODUCTION: Glioma is the most common malignant brain tumor. TP53 is the most common mutant gene in human cancer. Wild-type p53 (wtp53) is a tumor suppressor protein whereas mutant p53 (mutp53) is an oncoprotein that promotes tumor cell proliferation. Our aim was to examine the inhibitory effects of berberine on the proliferation of human glioma cells via regulation of wtp53, mutp53, and their downstream molecules. METHODS: We selected wtp53 cells (U87 cells) and mutp53 cells (U251 cells termed p53 R273H) to examine the inhibitory effects of berberine on human glioma cells. We used the CCK-8 kit to detect the toxic effect of berberine. Flow cytometry was used to detect the effect of berberine. Clone formation test was used to test the inhibitory effect of berberine on the proliferation of glioma cells. Western blot was used to detect the changes of related proteins such as p53, p-p53, p21 and cyclin D1. Lentivirus transduction was used to transduce wild-type p53 into U251 cells to further examine the effect of berberine. The nude mouse subcutaneous tumor model was used to detect the effect of berberine on inhibiting the proliferation of glioma cells in vivo. RESULTS: Berberine promoted the phosphorylation of wtp53, increased the expression of p21 protein, reduced cyclin D1 content, and caused G1 phase arrest in U87 cells. Berberine also reduced mutp53 content and caused G2 phase arrest in U251 cells with a concurrent decrease in p21, cyclin D1, and cyclin B1 content. Transduction with wtp53 enhanced the effects on cell cycle arrest. Further, berberine significantly inhibited glioma growth in vivo mouse tumor model. DISCUSSION: Glioma is a group of heterogeneous brain tumors with unique biological and clinical characteristics. Berberine can inhibit glioma cells through a variety of ways. Our research indicated that berberine inhibited the proliferation of glioma cells by interfering with wtp53 and mutp53. This indicates that berberine could be used as a potential drug to treat wild-type and mutant p53 glioma.