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

Abstract

Background

Glycogen synthase kinase 3 beta (GSK3β) is centrally involved in diverse cellular processes, including proliferation and apoptosis. This study aimed to investigate the influence of GSK3β expression on the prognosis of human non-small cell lung cancer (NSCLC) and the effects of GSK3β inhibition in NSCLC cell lines.

Methods

Immunohistochemical and western blot assays were used to evaluate the GSK3β expression level in human NSCLC tissues. Lentiviral RNA interference was performed to inhibit the expression of GSK3β 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 GSK3β 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 GSK3β expression was indicative of poor prognosis ( P = 0.006). Furthermore, knockdown of GSK3β 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 GSK3β attenuated tumorigenesis, as confirmed by reduced cell proliferation based on Ki-67 and significantly increased apoptotic cell death. The inhibition of GSK3β had inconsistent effects on the expression of β-catenin, depending on the cell type examined.

Conclusion

Aberrant expression of GSK3β serves as an independent marker of poor prognosis for NSCLC. The inhibition of GSK3β suppressed tumorigenesis by attenuating cell proliferation, increasing apoptosis and restraining cell motility. These results identify GSK3β as a tumor promoter and a potential therapeutic target in NSCLC.