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.
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.
Purpose
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
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.