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)3β has emerged as a multipotent therapeutic target in various diseases including
cancer. Here we investigated the biology and pathological role of GSK3β in ESCC and explored the
therapeutic effects of its inhibition. The expression of GSK3β 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. GSK3β-specific inhibitors and small interfering (si)
RNA-mediated knockdown of GSK3β attenuated
tumor cell survival and proliferation, while inducing apoptosis in ESCC cells and their xenograft
tumors in mice. GSK3β inhibition spared TYNEK-3 cells and the vital organs of mice. The
therapeutic effect of GSK3β 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 GSK3β is via
cyclin D1/CDK4-mediated cell cycle progression. Consequently, our study provides a biological rationale for GSK3β as a potential therapeutic target in ESCC.