Glycoprotein nonmetastatic melanoma protein B (GPNMB), which is involved in invasion and metastasis, was found to be overexpressed in various cancers. High levels of GPNMB and Na+/K+-ATPase alpha subunits are associated with a poor prognosis in glioblastoma patients. We showed that GPNMB interacts with Na+/K+-ATPase alpha subunits to activate PI3K/Akt and MEK/ERK pathways. However, it remains unclear whether the interaction of GPNMB and Na+/K+-ATPase alpha subunits is involves in progression of glioma. The tumor size induced by the injection of glioma GL261 cells was larger in transgenic mice over expressing GPNMB when compared with wild-type mice. Additionally, the interaction of GPNMB and Na+/K+-ATPase alpha subunits was identified in the murine glioma model and in the tumors of glioblastoma patients. Ouabain, a Na+/K+-ATPase inhibitor, suppressed the glioma growth induced by the injection of glioma cells in the transgenic mice overexpressing GPNMB and blocked the GPNMB-induced migration of glioma cells. These findings indicate that GPNMB promotes glioma growth via Na+/K+-ATPase alpha subunits. Thus, the interaction between GPNMB and Na+ ,K+-ATPase alpha subunits represents a novel therapeutic target for the treatment of brain glioblastomas. (C) 2016 Elsevier Inc. All rights reserved.