Downregulation of nitrogen permease regulator like‐2 activates PDK1‐AKT1 and contributes to the malignant growth of glioma cells

Abstract

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.

Trifluoperazine prevents FOXO1 nuclear excretion and reverses doxorubicin-resistance in the SHG44/DOX drug-resistant glioma cell line

“…Food and water were sterilized by high pressure steam and multivitamins were added into distilled water. The subcutaneous tumor model was produced as previously described ( 18 ). For treatment, 5 mg/kg DOX alone or 5 mg/kg DOX + 5 mg/kg/day TFP was injected the tail vein (DOX every 7 days and TFP every day).…”

“…For treatment, 5 mg/kg DOX alone or 5 mg/kg DOX + 5 mg/kg/day TFP was injected the tail vein (DOX every 7 days and TFP every day). Tumor volumes were recorded at 7, 14, 21 and 28 days post-implantation in accordance with the previously described formula ( 18 ).…”

Correlation of PDK1 expression with clinicopathologic features and prognosis of hepatocellular carcinoma

“…Lohneis et al 12 also pointed that PDK1 was an independent prognostic factor that is significantly negatively correlated to tumor grade in ovarian serous carcinoma. Moreover, other studies proved that PDK1 was correlated to prognosis of malignant gliomas, 13 breast cancer, 14 , 15 gall bladder cancer, 16 colorectal cancer, 17 and pancreatic cancer. 18 However, the relationship between PDK1 expression and prognosis of HCC has not yet been explored.…”

Overexpression of Nitrogen Permease Regulator Like-2 (NPRL2) Enhances Sensitivity to Irinotecan (CPT-11) in Colon Cancer Cells by Activating the DNA Damage Checkpoint Pathway

“…NPRL2 expression level was negatively correlated with the survival rate of patients with osteosarcoma and hepatocellular carcinoma (HCC), indicating its value as an independent prognostic marker [ 12 , 13 ]. Furthermore, intratumoral injection of a recombinant adenoviral or lentiviral vector containing NPRL2 gene significantly suppressed tumor growth and tumor progression and metastasis in various human lung cancer and glioma mouse models [ 10 , 14 ]. A prior evaluation revealed that NPRL2, as a molecular therapeutic target for enhancing and resensitizing the reaction to cisplatin, has been documented in lung cancer [ 15 , 16 ].…”

“…MMPs, in particular MMP2 and MMP9, are critical to tumor cell movement and invasion [ 26 ]. Huang et al documented that the down-regulation of NPRL2 stimulates PDK1-Akt1 and adds to the malignant development of glioma cells [ 14 ]. The PI3K/AKT pathway is a crucial signaling pathway that is responsible for cancer migration and invasion [ 27 ].…”