Whether AKT isoforms directly regulate the expression of N-myc in AbMole Mepiroxol neuroblastoma is unknown. Moreover, a role for GRP/GRP-R/AKT axis in the regulation of the MYCN oncogene in neuroblastoma is yet to be studied. In this study, we identified a novel regulation of N-myc expression by the AKT2 isoform in neuroblastoma cells. We also demonstrate that GRP-R regulates AKT2-mediatd N-myc expression. AbMole Riociguat BAY 63-2521 Interestingly, silencing AKT2 decreases neuroblastoma cell proliferation, anchorage-independent growth, migration and invasion, and VEGF secretion in vitro. Moreover, intrasplenic injection of AKT2 silenced neuroblastoma cells decreased the formation of liver metastases in vivo. Hence, we demonstrate that studying the GRP-R/AKT2/N-myc signaling axis may provide novel insights into the pathobiology of neuroblastoma tumorigenesis. In neuroblastoma,.50% of patients have metastatic disease at diagnosis, and thus creating major challenges for treatment and cure. Moreover, ‘high-risk’ group of neuroblastomas often relapse despite initial response to therapies. Frequently, tumors acquire drug resistance or aggressive phenotypes through the selection of rare resistant clones from heterogeneous tumor environment, which can result in major clinical obstacles in the treatment of neuroblastoma. Thus, a better understanding of the mechanisms of signaling pathways that contribute to metastasis may be valuable in the development of novel therapies. Oncogene MYCN is amplified and overexpressed in 25% of neuroblastoma patients, and correlates to poor outcomes in older children. PI3K/AKT pathway utilizes N-myc as a critical downstream effector to enhance tumorigenicity of neuroblastoma cells in vitro and in vivo. In this study, we found that silencing AKT2, but not AKT1 or AKT3 suppresses N-myc expression in neuroblastoma cells. This is a novel observation, implicating a specific AKT2 isoform as a critical regulator of Nmyc in neuroblastoma cells. Interestingly, a recent study has shown that MYCN contributes to tumorigenesis, in part, by repressing miR-184, and increasing AKT2 expression, a direct target of miR-184, and thereby indicating that AKT2 is a downstream target of N-myc. Overall, a positive regulatory loop might exist between the two oncogenic proteins, AKT2 and Nmyc in human neuroblastoma cells, which contributes crucially to tumorigenicity. Moreover, we also report, for the first time, that Nmyc expression can be regulated at the post-translational level by GRP-R, a GPCR involved in neuroblastoma tumorigenesis. Since, GRP-R silencing specifically inhibited the expression of AKT2 isoform, but not AKT1 or AKT3, we can further conclude that GRP-R-mediated regulation of N-myc expression in neuroblastoma cells is AKT2-dependent. We previously showed that a ratio of phosphorylated AKT to PTEN levels correlates with degree of differentiation in neuroblastomas; an increased ratio of AKT to PTEN expression was found in more undifferentiated tumors. Of the three AKT isoforms, AKT2 has been implicated more frequently in cancers. Consistent with other cancer cell types, we report, for the first time, that AKT2 is critical for neuroblastoma progression. AKT2 plays an important role in human neuroblastoma cells as a downstream target of GRP/GRP-R and regulates neuroblastoma cell proliferation, anchorage-independent growth, migration and invasion in vitro, implicating AKT2 in multiple aspects of neuroblastoma initiation and progression.