Gsk-3? Regulates Cellular Autophagy And Radiosensitivity In Non-small Cell Lung Cancer

Objective: Radiotherapy is one of the most common and effective treatment methods for cancer,and it is vital to improve radiosensitivity of tumor tissues during the treatment process.The goal of this study was to understand the mechanisms of GSK-3?-regulated autophagy and the effects of autophagy on radiosensitivity in non-small cell lung cancer.Methods: Immunohistochemical staining was performed to detect tissue GSK-3? expression in 89 non-small cell lung cancer(NSCLC)patient samples,for which follow-up data was available,and to determine the status of GSK-3? and autophagy markers after X-ray radiotherapy in NSCLC tissues.Western blot was used to quantitate expression changes in autophagy-related proteins after GSK-3? inhibitors were added to A549 cells,or after transfecting H460 cells with GSK-3? variants and subjecting them to X-ray irradiation.Clonogenic assays were used to measure the effect of autophagy on cellular proliferation.Results: GSK-3? expression positively correlated with NSCLC differentiation(P<0.05).After X-ray irradiation,GSK-3? and p62 expression was downregulated in NSCLC tissues,and the expression of the autophagy-related protein LC3 was significantly upregulated.After transfecting H460 cells with different GSK-3? mutants(wild type GSK-3?(GSK-3?-WT),constitutively active GSK-3?-S9 A,catalytically inactive GSK-3?-K85R)and subjecting these cells to X-ray irradiation,the expression of AMPK and LC3 decreased,whereas p62 expression increased;these effects were particularly significant with the GSK-3?-S9 A mutant.In A549 cells,after GSK-3? inhibition and X-ray irradiation,the expression of AMPK and LC3 proteins increased.When cellular autophagy was inhibited,cell proliferation decreased.Conclusion: GSK-3? expression is associated with NSCLC differentiation X-rays downregulate GSK-3? expression in some NSCLC cells and promote cellular autophagy.GSK-3? regulates autophagy,and inhibition of this process can enhance the radiosensitivity of NSCLC cells.