Downregulation of Nitrogen Permease Regulator Like-2 Activates PDK1-AKT1 and Contributes to the Malignant Growth of Glioma Cells

Nitrogen permease regulator like-2(NPRL2) is a candidate tumor suppressor gene(TSG) located on chromosome 3p21.3 and deletions frequently occur in this region, leading to canceration. Recently, molecular pathologic researches have provided valuable insights into the downregulation of NPRL2 in carcinogenesis in some types of cancers. However, very little is known about genetic changes of NPRL2 involved in glioma. Here, for the first time, we aimed to understand the expression levels, functions and mechanisms of NPRL2 for progression of glioma. We clearly demonstrated that NPRL2 expression was decreased in glioma and was negatively correlated with the histologic grade. The upregulation of NPRL2 expression in glioma cells inhibited proliferation by inducing G0/G1 cell cycle arrest in vitro and suppressed the growth of xenotransplanted tumors. In contrast, siRNA-mediated knockdown of NPRL2 promoted glioma growth. The anti-cancer effects of NPRL2 were involved in dephosphorylation of PDK1 and downstream AKT1 resulting in inactivation of the PDK1-AKT1 signaling pathway, this ultimately increased the expression of p21 and p27, and inactivated CDK2 and CDK4. Our data confirmed NPRL2 was downregulated in gliomas. More importantly, NPRL2 was able to inhibit cell proliferation in vitro and repress tumorigenicity in vivo, suggesting its role as a tumor suppressor. Our data provide a basis for the further development of a promising therapeutic target for glioma. © 2015 Wiley Periodicals, Inc.