Abstract
Activation of PI3K/AKT pathway correlates with poor prognosis in patients with neuroblastoma. Our previous studies have demonstrated that PI3K/AKT signaling is critical for the oncogenic transformations induced by gastrin-releasing peptide (GRP) and its receptor, GRP-R, in neuroblastoma. Moreover, PI3K/AKT-dependent oncogenic transformations require N-myc, an extensively studied oncogene in neuroblastoma. Whether AKT directly regulates the expression of N-myc oncogene is yet to be determined. Here, we report a novel finding that of the three AKT isoforms, AKT2 specifically regulated N-myc expression in neuroblastoma cells. We also confirmed that GRP-R is upstream of AKT2 and in turn, regulated N-myc expression via AKT2 in neuroblastoma cells. Functional assays demonstrated that attenuation of AKT2 impaired cell proliferation and anchorage-independent cell growth, and decreased the secretion of angiogenic factor VEGF in vitro. Furthermore, silencing AKT2 inhibited migration and invasion of neuroblastoma cells in vitro. Xenografts established by injecting AKT2 silenced human neuroblastoma cells into murine spleen expressed decreased levels of AKT2 and resulted in fewer liver metastases compared to controls in vivo. Hence, our study highlights the potential molecular mechanism(s) mediating the oncogenic role of GRP/GRP-R and demonstrates a novel role for AKT2 in neuroblastoma tumorigenesis, indicating that targeting the GRP/GRP-R/AKT2 axis may be important for developing novel therapeutics in the treatment of clinically aggressive neuroblastoma.
Highlights
Neuroblastoma is a pediatric neuroendocrine tumor that can produce and secrete a variety of neuropeptides, including gastrinreleasing peptide (GRP) [1]
We have previously reported that silencing GRP-R, a G-protein coupled receptor (GPCR), attenuated AKT signaling in neuroblastoma cells [13]
We found that silencing AKT2, but not AKT1 or AKT3 suppresses N-myc expression in neuroblastoma cells
Summary
Neuroblastoma is a pediatric neuroendocrine tumor that can produce and secrete a variety of neuropeptides, including gastrinreleasing peptide (GRP) [1]. GRP binds to G-protein coupled receptor, GRP-R, to stimulate growth of a number of normal and neoplastic tissues of the gastrointestinal tract, including neuroblastoma [2]. In spite of recent advances in understanding the role of GRP/GRP-R in tumor progression [3,4,5], signal transduction pathways regulated by GRP and its receptor are not completely understood. We have previously reported that the PI3K/AKT pathway, in part, mediates GRP-induced G1-S phase cell cycle progression and that bombesin, an amphibian equivalent of GRP, induces vascularization of neuroblastoma xenografts by upregulation of vascular endothelial growth factor (VEGF) [3,4]. Silencing GRP-R predominantly reduces AKT2 expression without affecting the expression of AKT1 or AKT3 isoform [13], demonstrating a more critical role of AKT2 in GRP-Rmediated neuroblastoma tumorigenesis. The exact role of AKT2 in neuroblastoma remains unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
