RRAGB-mediated suppression of PI3K/AKT exerts anti-cancer role in glioblastoma

Abstract

Glioblastoma (GBM) has a high degree of invasiveness, which is largely attributed to the invalidation of current therapy and the unclear tumor growth mechanism. Ras related GTP binding B (RRAGB) is a family member of the Ras-homologous GTPases. The effect of RRAGB on tumor growth has been recognized, but its influences on GBM progression are ill-defined. Here, in our research, a significantly decreased expression of RRAGB in GBM tissues by using TCGA databases and glioma samples is observed. According to Kaplan-Meier (KM) analysis, RRAGB low expression leads to a significant decrease of overall survival rate of patients, and is associated with the classification of WHO grade, histological type and age increase. Functional enrichment analysis reveals that the pathway of enrichment includes cell cycle arrest, extracellular matrix (ECM) processes and PI3K/AKT signal. Thereafter, our cell experiments confirm an obvious decrease of RRAGB in several GBM cell lines. It should be noted that RRAGB promotion strongly reduces the proliferation, migration and invasion of GBM cells and induces cell cycle arrest in G0/G1 phase. RRAGB up-regulation significantly decreases the expression of PI3K, phosphorylated AKT, mTOR and S6K in GBM cell lines. Surprisingly, we further find that RRAGB-restrained proliferative, migratory and invasive properties of GBM cells are markedly offset after promoting AKT activation, accompanied with restored phosphorylation of mTOR and S6K, elucidating that AKT signaling blockage is partially indispensable for RRAGB to play its anti-cancer role in GBM. Animal studies confirmed that RRAGB over-expression obviously inhibits the tumor growth both in the xenograft and orthotopic mouse glioma models, along with improved overall survival rates. In short, we provide evidence that RRAGB is a potential therapeutic target and prognostic marker for GBM treatment.