ENTPD5-mediated modulation of ATP results in altered metabolism and decreased survival in gliomablastoma multiforme

Abstract

Gliomablastoma multiforme (GBM) is the most aggressive of brain cancers in humans. Response to current therapies remains extremely poor, with dismal survival statistics. Recently, the endoplasmic reticulum UDPase, ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5), was identified as a key component in the Akt/phosphatidylinositol 3-kinase/phosphatase and tensin homolog regulatory loop, capable of synergizing aerobic glycolysis and cancer cell proliferation in vitro. Utilizing a novel enhanced acceptor fluorescence-based single-cell adenosine 5'-triphosphate (ATP) biosensor, we analyzed ENTPD5-mediated modulation of cytosolic ATP. Here, ENTPD5-dependent modulation of cellular ATP in GBM results in altered metabolic kinetics in vitro, increasing the catabolic efficiencies of aerobic glycolysis and fatty acid oxidation. Additionally, an upregulation of ENTPD5 in both GBM mouse xenografts and in GBM patient tumors was identified, resulting in dramatically reduced survival. Therefore, these results not only provide new tools to monitor ATP flux and cellular metabolism kinetics but also identified a novel therapeutic target for GBM.

miRNA and mRNA cancer signatures determined by analysis of expression levels in large cohorts of patients

“…Mammalian cell lines described in this study were purchased from American Type Culture Collection. Cell lines were maintained in standard conditions (33) The following cancer cell lines were used: human prostate carcinoma epithelial cell line (22RV1), human ovarian carcinoma cell line (OVCAR), adenocarcinomic human alveolar basal epithelial cells (A549), and human mammary carcinosarcoma cells lines (HS578T).…”

“…Cell proliferation was monitored at 1, 2, 3, and 4 d using a protocol described in ref. 33. At the end of each time period, the cells were trypsinized to produce a single-cell suspension, and the viable cell number in each well was counted using trypan blue (Gibco) to detect viable cells and a hemocytometer (LW Scientific).…”

RNA SEQ Analysis Indicates that the AE3 Cl−/HCO3 − Exchanger Contributes to Active Transport-Mediated CO2 Disposal in Heart

“…Smarcd3 is a transcriptional cofactor that drives glycolytic metabolism through a mechanism involving Akt 80 . Entpd5 , a UDPase, is involved in Akt responses and has been shown to increase the catabolic efficiency of aerobic glycolysis in tumor cells 81 . Ptk2b (Pyk2 tyrosine kinase, focal adhesion kinase 2) mediates insulin-independent insertion of GLUT4 into the plasma membrane 82 and contributes to α1-adrenergic receptor-mediated activation of Akt 83 .…”

NTPDase5/PCPH as a New Target in Highly Aggressive Tumors: A Systematic Review

“…Clinical samples of glioblastoma multiforme (GBMs) showed a higher level of NTPDase5 expression when compared to adjacent normal tissues [15]. In addition, the samples with higher expression levels of this protein were associated with significantly lower survival rates when compared to samples with lower NTPDase5 expression.…”

“…This protein plays a modulatory role in the bioenergetics of this malignancy, increasing the catabolic efficiency of the aerobic glycolysis. In addition, when NTPDase5 is suppressed, it causes a decrease in fatty acid oxidation and promotes an increase in the ATP influx and of the autophagic vacuoles in the cytoplasm [15]. …”