Potential therapeutic effect of targeting glycogen synthase kinase 3β in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is a common gastrointestinal cancer and is often refractory to current therapies. Development of efficient therapeutic strategies against ESCC presents a major challenge. Glycogen synthase kinase (GSK)3 beta has emerged as a multipotent therapeutic target in various diseases including cancer. Here we investigated the biology and pathological role of GSK3 beta in ESCC and explored the therapeutic effects of its inhibition. The expression of GSK3 beta and tyrosine (Y)216 phosphorylation-dependent activity was higher in human ESCC cell lines and primary tumors than untransformed esophageal squamous TYNEK-3 cells from an ESCC patient and tumor-adjacent normal esophageal mucosa. GSK3 beta -specific inhibitors and small interfering (si)RNA-mediated knockdown of GSK3 beta attenuated tumor cell survival and proliferation, while inducing apoptosis in ESCC cells and their xenograft tumors in mice. GSK3 beta inhibition spared TYNEK-3 cells and the vital organs of mice. The therapeutic effect of GSK3 beta inhibition in tumor cells was associated with G0/G1- and G2/M-phase cell cycle arrest, decreased expression of cyclin D1 and cyclin-dependent kinase (CDK)4 and increased expression of cyclin B1. These results suggest the tumor-promoting role of GSK3 beta is via cyclin D1/CDK4-mediated cell cycle progression. Consequently, our study provides a biological rationale for GSK3 beta as a potential therapeutic target in ESCC.