Potential therapeutic effect of targeting glycogen synthase kinase 3β in esophageal squamous cell carcinoma
| Autor: | Masahiro Uehara, Mitsutoshi Nakada, Itasu Ninomiya, Yoshio Endo, Tomoharu Miyashita, Richard W. Wong, Hemragul Sabit, Dilireba Bolidong, Takahiro Domoto, Toshinari Minamoto, Tomoyuki Okumura |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Adult
Male Cell biology Cell cycle checkpoint Esophageal Neoplasms Cell Survival Gene Expression lcsh:Medicine Antineoplastic Agents Apoptosis Article Mice Cyclin D1 GSK-3 Cyclin-dependent kinase Cell Line Tumor Biomarkers Tumor Animals Humans Medicine Molecular Targeted Therapy Neoplasm Metastasis Phosphorylation lcsh:Science Cyclin B1 Cancer Aged Cell Proliferation Neoplasm Staging Glycogen Synthase Kinase 3 beta Multidisciplinary biology business.industry Kinase lcsh:R Middle Aged medicine.disease Xenograft Model Antitumor Assays digestive system diseases Disease Models Animal biology.protein Cancer research Female lcsh:Q Esophageal Squamous Cell Carcinoma business Glycogen |
| Zdroj: | Scientific Reports, Vol 10, Iss 1, Pp 1-13 (2020) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-020-68713-9 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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