ENTPD5-mediated modulation of ATP results in altered metabolism and decreased survival in gliomablastoma multiforme
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RESEARCH ARTICLE
ENTPD5-mediated modulation of ATP results in altered metabolism and decreased survival in gliomablastoma multiforme Sohila Zadran & Arash Amighi & Erick Otiniano & Kaylee Wong & Homera Zadran
Received: 8 August 2012 / Accepted: 28 August 2012 / Published online: 20 September 2012 # International Society of Oncology and BioMarkers (ISOBM) 2012
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 ENTPD5mediated modulation of cytosolic ATP. Here, ENTPD5dependent 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. Keywords ENTPD5 . Single-cell EAF-based ATP sensor . Metabolomics . Glioblastoma multiforme Statement of significance: Utilizing a novel enhanced acceptor fluorescence-based single-cell ATP biosensor, ENTPD5-mediated modulation of cytosolic ATP alters metabolic kinetics. ENTPD5 is identified as a new therapeutic target for GBM. S. Zadran (*) : A. Amighi : E. Otiniano : K. Wong : H. Zadran 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 e-mail: [email protected]
Introduction Glioblastoma multiforme (GBM) is an aggressive primary brain tumor that exhibits extremely poor response to current therapies. Despite maximal therapy with surgical resection, radiation, and temozolomide, survival statistics remain dismal. GBM are very vascular tumors with remarkable molecular and genetic heterogeneity. Phosphatidylinositol 3-kinase (PI3K) signaling is hyperactivated in nearly 90 % of GBMs, most frequently in association with epidermal growth factor receptor amplification and mutation and loss of the phosphatase and tensin homolog (PTEN) tumor suppressor protein. Additionally, GBM has a strong glycolytic phenotype, with GBM U87 and U87vIII cells lines displaying both a high glycolytic rate with increased lactic acid production and impaired mitochondrial respiratory function [1, 2]. Warburg first demonstrated that the metabolism of cancer cells, even under normoxia, is characterized by an increase in the ratio o
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