14-3-3β regulates the proliferation of glioma cells through the GSK3β/β-catenin signaling pathway.

We previously demonstrated that 14-3-3β is overexpressed in astrocytomas; however, the underlying mechanisms are poorly understood. Based on the reported multiple functions of 14-3-3β, we hypothesized that it interacts with glycogen synthase kinase 3 β (GSK3β), which regulates β-catenin-mediated oncogene expression and contributes to tumorigenesis and astrocytoma progression. To test these hypotheses, we used 14-3-3β overexpression vectors and small interfering RNA (siRNA) transfection in the human normal astrocyte cell line SVGp12 and the glioma cell line U87, respectively. The results showed that overexpression of 14-3-3β promoted the proliferation of SVGp12 cells, while knockdown of 14-3-3β inhibited the proliferation of U87 cells as analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and bromodeoxyuridine (BrdU) assays. In Flag-tagged 14-3-3β-overexpressing cells, GSK3β was co-immunoprecipitated with 14-3-3β using a Flag antibody. Knockdown of β-catenin by siRNA blocked cell proliferation induced by overexpression of 14-3-3β. Furthermore, overexpression of 14-3-3β suppressed the phosphorylation of β-catenin leading to its accumulation and nuclear translocation as revealed by western blot analysis. In addition, β-catenin nuclear translocation induced by overexpression of 14-3-3β activated the transcription of oncogenes including c-myc and cyclin D1. Collectively, these results revealed that 14-3-3β regulates the proliferation of astrocytes and glioma cells through the GSK3β/β-catenin signaling pathway. The delineated mechanism of 14-3-3β may be responsible for the tumorigenesis and progression of human astrocytomas. Thus, new therapeutic strategies or drugs aimed at 14-3-3β may have potential for the treatment of human astrocytomas.