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      Tumor Metabolism of Malignant Gliomas

      review-article
      Author(s): , , , *
      Publication date (Electronic):
      Journal: Cancers
      Publisher: MDPI
      Keywords: glioblastoma, tumor metabolism, SREBP-1, LDLR, LXR, glucose, lipids, cholesterol

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          Abstract

          Constitutively activated oncogenic signaling via genetic mutations such as in the EGFR/PI3K/Akt and Ras/RAF/MEK pathways has been recognized as a major driver for tumorigenesis in most cancers. Recent insights into tumor metabolism have further revealed that oncogenic signaling pathways directly promote metabolic reprogramming to upregulate biosynthesis of lipids, carbohydrates, protein, DNA and RNA, leading to enhanced growth of human tumors. Therefore, targeting cell metabolism has become a novel direction for drug development in oncology. In malignant gliomas, metabolism pathways of glucose, glutamine and lipid are significantly reprogrammed. Moreover, molecular mechanisms causing these metabolic changes are just starting to be unraveled. In this review, we will summarize recent studies revealing critical gene alterations that lead to metabolic changes in malignant gliomas, and also discuss promising therapeutic strategies via targeting the key players in metabolic regulation.

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          Most cited references76

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          On the origin of cancer cells.

          O WARBURG (1956)
          Article 0 comments Cited 2462 times – based on 0 reviews     Review now
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            ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect

            Weiwei Yang, Yanhua Zheng, Yan Xia … (2012)
            SUMMARY Pyruvate kinase M2 (PKM2) is upregulated in multiple cancer types and contributes to the Warburg effect by unclarified mechanisms. Here we demonstrate that EGFR-activated ERK2 binds directly to PKM2 I429/L431 via the ERK2 docking groove and phosphorylates PKM2 Ser37 but not PKM1. Phosphorylated PKM2 Ser37 recruits PIN1 for cis-trans isomerization of PKM2, which leads to PKM2 binding to importin α5 and nuclear translocation. Nuclear PKM2, acting as a coactivator of β-catenin, induces c-Myc expression, resulting in the upregulation of GLUT1, LDHA, and, in a positive feedback loop, PTB-dependent PKM2 expression. Replacement of wild type PKM2 with a nuclear translocation-deficient mutant (S37A) blocks the EGFR-promoted Warburg effect and brain tumor development. In addition, levels of PKM2 S37 phosphorylation correlate with EGFR and ERK1/2 activity in human glioblastoma specimens. Our findings highlight the importance of nuclear functions of PKM2 in the Warburg effect and tumorigenesis.
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              Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function.

              John E. Wilson (2003)
              The first step in metabolism of glucose (Glc) is usually phosphorylation, catalyzed by hexokinase. However, the Glc-6-P produced can then enter one or more of several alternative pathways. Selective expression of isozymic forms of hexokinase, differing in catalytic and regulatory properties as well as subcellular localization, is likely to be an important factor in determining the pattern of Glc metabolism in mammalian tissues/cells. Despite their overall structural similarity, the Type I, Type II and Type III isozymes differ in important respects. All three isozymes are inhibited by the product, Glc-6-P, but with the Type I isozyme, this inhibition is antagonized by P(I), whereas with the Type II and Type III isozymes, P(i) actually causes additional inhibition. Reciprocal changes in intracellular levels of Glc-6-P and P(i) are closely associated with cellular energy status, and it is proposed that the response of the Type I isozyme to these effectors adapts it for catabolic function, introducing Glc into glycolytic metabolism for energy production. In contrast, the Type II, and probably the Type III, isozymes are suggested to serve primarily anabolic functions, e.g. to provide Glc-6-P for glycogen synthesis or metabolism via the pentose phosphate pathway for lipid synthesis. Type I hexokinase binds to mitochondria through interaction with porin, the protein that forms channels through which metabolites traverse the outer mitochondrial membrane. Several experimental approaches have led to the conclusion that the Type I isozyme, bound to actively phosphorylating mitochondria, selectively uses intramitochondrial ATP as substrate. Such interactions are thought to facilitate coordination of the introduction of Glc into glycolysis, via the hexokinase reaction, with the terminal oxidative stages of Glc metabolism occurring in the mitochondria, thus ensuring an overall rate of Glc metabolism commensurate with cellular energy demands and avoiding excessive production of lactate. The Type II isozyme also binds to mitochondria. Whether such coupling occurs with mitochondrially bound Type II hexokinase in normal tissues, and how it might be related to the proposed anabolic role of this isozyme, remain to be determined. The Type III isozyme lacks the hydrophobic N-terminal sequence known to be critical for binding of the Type I and Type II isozymes to mitochondria. Immunolocalization studies have indicated that, in many cell types, the Type III has a perinuclear localization, the possible metabolic consequences of which remain unclear.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cancers (Basel)
                Journal ID (iso-abbrev): Cancers (Basel)
                Journal ID (publisher-id): cancers
                Title: Cancers
                Publisher: MDPI
                ISSN (Electronic): 2072-6694
                Publication date (Electronic): 08 November 2013
                Publication date Collection: December 2013
                Volume: 5
                Issue: 4
                Pages: 1469-1484
                Affiliations
                Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center & Arthur G James Cancer Hospital, Columbus, OH 43012, USA; E-Mails: peng.ru@ 123456osumc.edu (P.R.); terence.williams@ 123456osumc.edu , (T.M.W.); arnab.chakravarti@ 123456osumc.edu (A.C.)
                Author notes
                [* ] Author to whom correspondence should be addressed; E-Mail: deliang.guo@ 123456osumc.edu ; Tel.: +1-614-366-3774; Fax: +1-614-247-1877.
                Article
                Publisher ID: cancers-05-01469
                DOI: 10.3390/cancers5041469
                PMC ID: 3875949
                PubMed ID: 24217114
                SO-VID: 9405788f-2a2c-431b-9e4e-8cc454a23841
                Copyright © © 2013 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 22 October 2013
                Date accepted : 24 October 2013
                Categories
                Subject: Review

                Keywords: glioblastoma,tumor metabolism,srebp-1,ldlr,lxr,glucose,lipids,cholesterol
                Data availability:
                Keywords: glioblastoma, tumor metabolism, srebp-1, ldlr, lxr, glucose, lipids, cholesterol

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