A GAD1 inhibitor suppresses osteosarcoma growth through the Wnt/ß-catenin signaling pathway.

ABSTRACT

Background: As a marker of the GABAergic system, the expression of glutamate decarboxylase 1 (GAD1) is mainly restricted to the central nervous system. Emerging studies have shown that aberrant expression of GAD1 in tumor tissues may promote tumor cell growth. The role of GAD1 in the development of osteosarcoma (OS) remains unclear, so this study sought to investigate the expression status of GAD1 and the effect of its specific inhibitor 3-mercaptopropionic acid (3-MPA) on OS. Methods: The R2 database was used to analyze the relationship between the expression of GAD1 and clinical prognosis in OS patients. Immunohistochemistry was used to compare the expression profile of GAD1 between OS and matched neighboring tissues. The potential antitumor effects of 3-MPA on cell viability, colony formation and the cell cycle were examined. Moreover, the in vivo effect of 3-MPA on tumor growth was investigated using tumor-bearing nude mice. Results: The expression level of GAD1 was aberrantly upregulated in OS tissues, but almost no expression of GAD1 was found in matched neighboring tissues. Western blotting analyses showed upregulation of GAD1 in OS cells compared to human osteoblast cells. In vitro and in vivo, 3-MPA significantly suppressed the growth of OS. Regarding the mechanism, 3-MPA inhibited ß-catenin and cyclin D1 in OS cells, thereby inactivating the Wnt/ß-catenin pathway. Conclusions: OS displays increased expression of the GABAergic neuronal marker GAD1, and 3-MPA significantly reduces OS growth by inhibiting the Wnt/ß-catenin pathway.