GSK3β Overexpression Indicates Poor Prognosis and Its Inhibition Reduces Cell Proliferation and Survival of Non-Small Cell Lung Cancer Cells

Background: Glycogen synthase kinase 3 beta (GSK3 beta) is centrally involved in diverse cellular processes, including proliferation and apoptosis. This study aimed to investigate the influence of GSK3 beta expression on the prognosis of human non-small cell lung cancer (NSCLC) and the effects of GSK3 beta inhibition in NSCLC cell lines. Methods: Immunohistochemical and western blot assays were used to evaluate the GSK3 beta expression level in human NSCLC tissues. Lentiviral RNA interference was performed to inhibit the expression of GSK3 beta in the A549, H292, H1299 and SK-MES-1 cell lines. Cell survival, apoptosis and motility were evaluated in vivo and in vitro. Results: The levels of GSK3 beta were greater in NSCLC tissues (n = 211) than in control tissues (n = 194) (P<0.001). The 5-year follow-up analysis showed that positive GSK3 beta expression was indicative of poor prognosis (P = 0.006). Furthermore, knockdown of GSK3 beta in NSCLC cell lines suppressed cell proliferation, arrested tumor cells in G0/G1 phase, induced apoptosis and reduced cell motility. A xenograft model showed that the deregulation of GSK3 beta attenuated tumorigenesis, as confirmed by reduced cell proliferation based on Ki-67 and significantly increased apoptotic cell death. The inhibition of GSK3 beta had inconsistent effects on the expression of beta-catenin, depending on the cell type examined. Conclusion: Aberrant expression of GSK3 beta serves as an independent marker of poor prognosis for NSCLC. The inhibition of GSK3 beta suppressed tumorigenesis by attenuating cell proliferation, increasing apoptosis and restraining cell motility. These results identify GSK3 beta as a tumor promoter and a potential therapeutic target in NSCLC.