Inhibition of glycogen synthase kinase 3 beta (GSK3) suppresses the progression of esophageal squamous cell carcinoma by modifying STAT3 activity

Although GSK3 has been reported to have contrasting effects on the progression of different tumors, it's possible functions in esophageal squamous cell carcinoma (ESCC) and the related molecular mechanisms remain unknown. Here, we investigated the expression, function, and molecular mechanism of GSK3 in the development of ESCC in vitro and in vivo. Though the expression of total GSK3 was significantly increased, the phosphorylated (inactivated) form of GSK3 (Ser9) was concurrently decreased in the cancerous tissues of patients with ESCC compared with controls, suggesting that GSK3 activity was enhanced in cancerous tissues. Further pathological data analysis revealed that higher GSK3 expression was associated with poorer differentiation, higher metastasis rates, and worse prognosis of ESCC. These results were confirmed in different ESCC cell lines using a pharmacological inhibitor and specific siRNA to block GSK3. Using a cancer phospho-antibody array, we found that STAT3 is a target of GSK3. GSK3 inhibition reduced STAT3 phosphorylation, and overexpression of constitutively active GSK3 had the opposite effect. Moreover, STAT3 inhibition mimicked the effects of GSK3 inhibition on ESCC cell migration and viability, while overexpression of a plasmid encoding mutant STAT3 (Y705F) abrogated these effects, and these results were further substantiated by clinicopathological data. In addition, a GSK3 inhibitor (LiCl) and/or STAT3 inhibitor (WP-1066) efficiently suppressed the growth of ESCC cells in a xenograft tumor model. Altogether, these results reveal that higher GSK3 expression promotes ESCC progression through STAT3 in vitro and in vivo, and GSK3-STAT3 signaling could be a potential therapeutic target for ESCC treatment.