Glycogen Synthase Kinase 3 Promotes Tyrosine Kinase Inhibitor-Induced Apoptosis in Philadelphia Chromosome-Positive Leukemia Cells by Regulating the Wnt/β-Catenin Pathway

Abstract

Background: Tyrosine kinase inhibitors (TKIs) have been used as first-line therapy drugs for the treatment of Philadelphia chromosome-positive (Ph+) leukemia, although some patients develop drug resistance. The present study investigates the role of glycogen synthase kinase 3 (GSK3) in Ph+ leukemia cells treated with TKIs. Methods: K562 and Ku812 leukemia cells were treated with TKIs (imatinib or dasatinib) and GSK3 inhibitors (SB216763 and lithium chloride). The cell counting kit-8 (CCK-8) was employed to evaluate cell viability, while cell apoptosis was quantified by flow cytometry. The expression of apoptotic proteins was assessed using Western blot. The expressions of GSK3α and GSK3β in K562 cells were knocked down using lentivirus plasmids. TOP/FOP flash assay was performed to detect the transcriptional activity of Wnt/β-catenin. Results: SB216763 and lithium chloride increased cell viability and decreased cell apoptosis induced by imatinib (IM) and dasatinib (DA) in K562 and Ku812 cells. Knockdown of GSK3α and GSK3β inhibited apoptosis and promoted the viability of K562 cells induced by TKIs. Knockdown of GSK3α and GSK3β also reversed the decrease in TOP/FOP ratio induced by IM and DA. Conclusion: GSK3 promotes TKI-induced apoptosis in Ph+ leukemia cells, and may be related to the inhibition of the Wnt/β-catenin pathway. GSK3α and GSK3β were both involved in Ph+ leukemia, indicating that GSK3 is a tumor suppressor.