Oligodendroglioma cells lack glutamine synthetase and are auxotrophic for glutamine, but do not depend on glutamine anaplerosis for growth

Chiu, M., Taurino, G., Bianchi, M. G., Ottaviani, L., Andreoli, R., Ciociola, T., Lagrasta, C. A. M., Tardito, S. and Bussolati, O. (2018) Oligodendroglioma cells lack glutamine synthetase and are auxotrophic for glutamine, but do not depend on glutamine anaplerosis for growth. International Journal of Molecular Sciences, 19(4), 1099. (doi: 10.3390/ijms19041099) (PMID:29642388) (PMCID:PMC5979401)

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Abstract

In cells derived from several types of cancer, a transcriptional program drives high consumption of glutamine (Gln), which is used for anaplerosis, leading to a metabolic addiction for the amino acid. Low or absent expression of Glutamine Synthetase (GS), the only enzyme that catalyzes de novo Gln synthesis, has been considered a marker of Gln-addicted cancers. In this study, two human cell lines derived from brain tumors with oligodendroglioma features, HOG and Hs683, have been shown to be GS-negative. Viability of both lines depends from extracellular Gln with EC of 0.175 ± 0.056 mM (Hs683) and 0.086 ± 0.043 mM (HOG), thus suggesting that small amounts of extracellular Gln are sufficient for OD cell growth. Gln starvation does not significantly affect the cell content of anaplerotic substrates, which, consistently, are not able to rescue cell growth, but causes hindrance of the Wnt/β-catenin pathway and protein synthesis attenuation, which is mitigated by transient GS expression. Gln transport inhibitors cause partial depletion of intracellular Gln and cell growth inhibition, but do not lower cell viability. Therefore, GS-negative human oligodendroglioma cells are Gln-auxotrophic but do not use the amino acid for anaplerosis and, hence, are not Gln addicted, exhibiting only limited Gln requirements for survival and growth.

Item Type:Articles
Additional Information:This work was supported by the University of Parma. The contribution of prof. Enrico M. Silini in the evaluation of IDH1/2 status of oligodendroglioma cells and in the interpretation of experimental data is gratefully acknowledged. Saverio Tardito is supported by Cancer Research UK (C596/A17196, Award 23982). Martina Chiu is at present supported by a fellowship of the Associazione Italiana per la Ricerca sul Cancro (AIRC 19272) at the Laboratory of Hematology, Department of Medicine and Surgery, University of Parma. The confocal images were obtained in the Laboratory of Confocal Microscopy of the Department of Medicine and Surgery of the University of Parma.
Keywords:Anaplerosis, beta-catenin, glutamine, glutamine addiction, glutamine transport, oligodendroglioma.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Tardito, Dr Saverio
Authors: Chiu, M., Taurino, G., Bianchi, M. G., Ottaviani, L., Andreoli, R., Ciociola, T., Lagrasta, C. A. M., Tardito, S., and Bussolati, O.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:International Journal of Molecular Sciences
Publisher:MDPI
ISSN:1661-6596
ISSN (Online):1422-0067
Published Online:06 April 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in International Journal of Molecular Sciences 19(4):1099
Publisher Policy:Reproduced under a Creative Commons License

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