Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) has been recently identified as a novel inhibitor of multiple tumors; however, its role in glioblastoma (GBM) has not been investigated. This study aimed to evaluate whether LHPP exerts a potential tumor-inhibiting role in GBM. Compared with that in normal tissues, LHPP expression was lower in GBM tissues and various GBM cell lines. LHPP up-regulation in GBM cells markedly reduced their proliferation and invasion, and its knockdown had an oncogenic effect on these cells. Further studies revealed that overexpressed LHPP decreased the levels of Akt and glycogen synthase-3β phosphorylation and down-regulated Wnt/β-catenin signaling. By contrast, LHPP knockdown produced opposite effects. Akt suppression markedly abrogated the activation of Wnt/β-catenin signaling induced by LHPP knockdown. The reactivation of Wnt/β-catenin signaling partially reversed the inhibition of tumor growth in GBM mediated by LHPP overexpression. In addition, LHPP overexpression markedly retarded the tumorigenesis of GBM cells in vivo. These findings revealed that LHPP acts a potential inhibitor of tumor growth in GBM, and its overexpression represses GBM proliferation and invasion by down-regulating Akt and Wnt/β-catenin signaling. This work highlights the crucial role of LHPP in GBM progression and suggests its potential as an anticancer target for the treatment of this disease.
Keywords: Akt; GSK-3β; Glioblastoma; LHPP.