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      Metabolic response of glioblastoma cells associated with glucose withdrawal and pyruvate substitution as revealed by GC-MS

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          Abstract

          Background

          Tumor cells are highly dependent on glucose even in the presence of oxygen. This concept called the Warburg effect is a hallmark of cancer and strategies are considered to therapeutically exploit the phenomenon such as ketogenic diets. The success of such strategies is dependent on a profound understanding of tumor cell metabolism. With new techniques it is now possible to thoroughly analyze the metabolic responses to the withdrawal of substrates and their substitution by others. In the present study we used gas chromatography coupled to mass spectrometry (GC-MS) to analyze how glioblastoma brain tumor cells respond metabolically when glucose is withdrawn and substituted by pyruvate.

          Methods

          Glioblastoma brain tumor cells were cultivated in medium with high (25 mM), medium (11 mM) or low (5.5 mM) glucose concentration or with pyruvate (5 mM). After 24 h GC-MS metabolite profiling was performed.

          Results

          The abundances of most metabolites were dependent on the supply of glucose in tendency but not in a linear manner indicating saturation at high glucose. Noteworthy, a high level of sorbitol production and release was observed at high concentrations of glucose and high release of alanine, aspartate and citrate were observed when glucose was substituted by pyruvate. Intermediates of the TCA cycle were present under all nutritional conditions and evidence was found that cells may perform gluconeogenesis from pyruvate.

          Conclusions

          Our experiments reveal a high plasticity of glioblastoma cells to changes in nutritional supply which has to be taken into account in clinical trials in which specific diets are considered for therapy.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12986-016-0131-9) contains supplementary material, which is available to authorized users.

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          Most cited references23

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          On the origin of cancer cells.

          O WARBURG (1956)
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            Hypoxia signalling through mTOR and the unfolded protein response in cancer.

            Hypoxia occurs in the majority of tumours, promoting angiogenesis, metastasis and resistance to therapy. Responses to hypoxia are orchestrated in part through activation of the hypoxia-inducible factor family of transcription factors (HIFs). Recently, two additional O(2)-sensitive signalling pathways have also been implicated: signalling through the mammalian target of rapamycin (mTOR) kinase and signalling through activation of the unfolded protein response (UPR). Although they are activated independently, growing evidence suggests that HIF-, mTOR- and UPR-dependent responses to hypoxia act in an integrated way, influencing each other and common downstream pathways that affect gene expression, metabolism, cell survival, tumorigenesis and tumour growth.
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              Origin of the U87MG glioma cell line: Good news and bad news.

              Human tumor-derived cell lines are indispensable tools for basic and translational oncology. They have an infinite life span and are easy to handle and scalable, and results can be obtained with high reproducibility. However, a tumor-derived cell line may not be authentic to the tumor of origin. Two major questions emerge: Have the identity of the donor and the actual tumor origin of the cell line been accurately determined? To what extent does the cell line reflect the phenotype of the tumor type of origin? The importance of these questions is greatest in translational research. We have examined these questions using genetic profiling and transcriptome analysis in human glioma cell lines. We find that the DNA profile of the widely used glioma cell line U87MG is different from that of the original cells and that it is likely to be a bona fide human glioblastoma cell line of unknown origin.
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                Author and article information

                Contributors
                +49 341 97- 22145 , henry.oppermann@medizin.uni-leipzig.de
                yonghong.ding@yahoo.com
                jeevan.pharma@yahoo.com
                Mandy.Berndt@medizin.uni-leipzig.de
                Juergen.Meixensberger@medizin.uni-leipzig.de
                Frank.Gaunitz@medizin.uni-leipzig.de
                birkemeyer@chemie.uni-leipzig.de
                Journal
                Nutr Metab (Lond)
                Nutr Metab (Lond)
                Nutrition & Metabolism
                BioMed Central (London )
                1743-7075
                18 October 2016
                18 October 2016
                2016
                : 13
                : 70
                Affiliations
                [1 ]Klinik und Poliklinik für Neurochirurgie, Universitätsklinikum Leipzig AöR, Liebigstraße 19, Leipzig, 04103 Germany
                [2 ]Institut für Analytische Chemie, Fakultät für Chemie & Mineralogie der Universität Leipzig, Linnéstraße 3, Leipzig, 04103 Germany
                Author information
                http://orcid.org/0000-0001-9216-5918
                Article
                131
                10.1186/s12986-016-0131-9
                5070012
                235a1d87-af19-4414-a536-d6108d19072d
                © The Author(s). 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 5 August 2016
                : 8 October 2016
                Funding
                Funded by: junior research grant of the Medical Faculty of the University of Leipzig
                Funded by: European Fund for Structural Development EFRE
                Award ID: 22137019
                Award Recipient :
                Funded by: Erasmus Mundus Programme at the UL
                Award ID: 1298/2008/EC
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2016

                Nutrition & Dietetics
                cancer,glucose,pyruvate,metabolite profiling,glioblastoma,warburg effect
                Nutrition & Dietetics
                cancer, glucose, pyruvate, metabolite profiling, glioblastoma, warburg effect

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