OncoTargets and Therapy (Nov 2019)
Inhibition Of Glycogen Synthase Kinase 3 Beta Suppresses The Growth And Survival Of Skull Base Chordoma Cells By Downregulating Brachyury Expression
Abstract
Xudong Yan,1 Zhiyuan Li,2 Hong Li,3 Pei Liu,4 Zehang Zhao,5 Shan Cheng,5 Zhenlin Wang,1 Qiuhang Zhang1 1Department of Otolaryngology-Head and Neck Surgery, Skull Base Surgery Center, Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Key Laboratory, Department of Otolaryngology-Head and Neck Surgery, Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 3Department of Pathology, Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 4Department of Anesthesiology, Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 5Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Qiuhang ZhangDepartment of Otolaryngology-Head and Neck Surgery, Skull Base Surgery Center, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Xicheng, Beijing 100053, People’s Republic of ChinaEmail [email protected]: Chordomas are locally aggressive tumors arising from notochordal remnants. Brachyury, a protein coded by T-gene, is crucial for chordoma cell proliferation. The aim of this study was to evaluate the effects of glycogen synthase kinase 3 beta (GSK3β) activity on brachyury expression and on the growth and survival of skull base chordoma cells.Patients and methods: In this study, 16 paraffin-embedded specimens of primary skull base chordomas were analyzed for the expression of phosphorylated GSK3β and brachyury using immunohistochemistry. The UM-Chor1 cell line derived from a clival chordoma was treated with AR-A014418 (AR), an inhibitor of GSK3β, and brachyury expression was analyzed by qRT-PCR and Western blotting. The possible mechanism by which brachyury regulates the Wnt/β-catenin signaling pathway was investigated by immunocytochemistry. The effects of AR on cell proliferation as well as sensitivity to chemotherapeutic drugs were also examined.Results: The results suggested that phosphorylated GSK3β and brachyury were upregulated in chordoma tissues. The GSK3β inhibitor (AR) decreased brachyury expression and suppressed the growth and survival of the chordoma cells, possibly via regulation of the Wnt/β-catenin signaling pathway. Moreover, AR increased the sensitivity of chordoma cells to chemotherapeutic drugs in vitro.Conclusion: This study provides evidence for the clinical development of the GSK3β inhibitor (AR-A014418) as a potential chemotherapeutic adjuvant for the treatment of chordoma.Keywords: GSK3β inhibitor, skull base chordoma, brachyury, Wnt/β-catenin signaling pathway
