title: 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.
authors.affiliation: David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Ave, Center for the Health Sciences, Room CHS 33-165, Los Angeles, CA 90095, USA. szadran@mednet.ucla.edu
authors.forename: Sohila
authors.initials: S
authors.lastname: Zadran
authors.forename: Arash
authors.initials: A
authors.lastname: Amighi
authors.forename: Erick
authors.initials: E
authors.lastname: Otiniano
authors.forename: Kaylee
authors.initials: K
authors.lastname: Wong
authors.forename: Homera
authors.initials: H
authors.lastname: Zadran
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D049109:Cell Proliferation; D005909:Glioblastoma / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D007124:Immunoenzyme Techniques; D019344:Lactic Acid / Q000378:metabolism; D050356:Lipid Metabolism; D051379:Mice; D053758:Nanoparticles; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption; D011379:Prognosis; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D015513:Oncogene Proteins; D034741:RNA, Small Interfering; D019344:Lactic Acid; D000255:Adenosine Triphosphate; C117634:ENTPD5 protein, human; D011755:Pyrophosphatases; D005947:Glucose