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

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Tumor Biology

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.

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Acknowledgments

The technical aid of Shaojun Zhu, Huijun Yang, Dr. Sirus Kohan, and Ms. Birgitta Sjostrand in experiments was appreciated. Additionally, suggestions provided by Dr. Laurent Vergnes in XF Seahorse Analyzer experiments and Dr. Sergey Marniov and UCLA Brain Tumor Translational Resource for biospecimen and biorepository support were also greatly appreciated. The guidance and experimental suggestions were provided by Dr. James Heath and Dr. Raphael Levine for this project. The UCLA Department of Pathology and Laboratory Medicine and the David Geffen School of Medicine provided early career award and financial support for the project.

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Authors and Affiliations

  1. 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

    Sohila Zadran, Arash Amighi, Erick Otiniano, Kaylee Wong & Homera Zadran

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  1. Sohila Zadran
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  2. Arash Amighi
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  3. Erick Otiniano
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  4. Kaylee Wong
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  5. Homera Zadran
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Corresponding author

Correspondence to Sohila Zadran.

Additional information

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.

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Zadran, S., Amighi, A., Otiniano, E. et al. ENTPD5-mediated modulation of ATP results in altered metabolism and decreased survival in gliomablastoma multiforme. Tumor Biol. 33, 2411–2421 (2012). https://doi.org/10.1007/s13277-012-0505-1

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  • DOI: https://doi.org/10.1007/s13277-012-0505-1

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