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Osteosarcoma is one of the most aggressive types of primary bone cancer that responds poorly to radiotherapy frequently. The gene associated with retinoid-interferon mortality (GRIM-19) is a tumor suppressor that mediates cell apoptosis in multiple cancer types. However, the role of GRIM-19 in osteosarcoma and the underlying mechanism remain unclear. This study was designed to investigate the role and the underlying mechanism of GRIM-19 in osteosarcoma progression.Osteosarcoma tissues and cell lines were utilized to analyze the expressions of GRIM-19 in osteosarcoma by qRT-PCR and Western blot. Methods containing flow cytometry, irradiation exposure, cells inoculation, plasmid transfection, and protein immunoprecipitation were used to investigate the underlying mechanisms of GRIM-19 in osteosarcoma progression.GRIM-19 is downregulated in osteosarcoma tissues and cell lines. Exposure to radiation induces osteosarcoma cell apoptosis by upregulation of p53 both in U2OS (p53-wt) and exogenous p53-introduced MG-63 (p53-null) osteosarcoma cells. Overexpression of GRIM-19 accelerates radiation-induced osteosarcoma cells apoptosis by p53 stabilization ex vivo and in vivo. Mechanistically, forced expression of GRIM-19 diminishes the activity of E3 ubiquitin-protein ligase mouse double minute 2 homolog (MDM2), a specific p53 protease, results in the accumulation of p53 and activation of p53-mediated apoptosis.GRIM-19 was proved to modulate radiation-induced osteosarcoma cells apoptosis in a p53 dependent manner by mediating MDM2 activity, which sheds light on the development of GRIM-19-based molecular target therapy on osteosarcoma.