Reverse TCA cycle flux through isocitrate dehydrogenases 1 and 2 is required for lipogenesis in hypoxic melanoma cells

Sanford-Burnham Medical Research Institute, Cancer Research Center, La Jolla, CA, USA.
Pigment Cell & Melanoma Research (Impact Factor: 5.64). 02/2012; 25(3):375-83. DOI: 10.1111/j.1755-148X.2012.00989.x
Source: PubMed

ABSTRACT The tricarboxylic acid (TCA) cycle is the central hub of oxidative metabolism, running in the classic forward direction to provide carbon for biosynthesis and reducing agents for generation of ATP. Our metabolic tracer studies in melanoma cells showed that in hypoxic conditions the TCA cycle is largely disconnected from glycolysis. By studying the TCA branch point metabolites, acetyl CoA and citrate, as well as the metabolic endpoint glutamine and fatty acids, we developed a comprehensive picture of the rewiring of the TCA cycle that occurs in hypoxia. Hypoxic tumor cells maintain proliferation by running the TCA cycle in reverse. The source of carbon for acetyl CoA, citrate, and fatty acids switches from glucose in normoxia to glutamine in hypoxia. This hypoxic flux from glutamine into fatty acids is mediated by reductive carboxylation. This reductive carboxylation is catalyzed by two isocitrate dehydrogenases, IDH1 and IDH2. Their combined action is necessary and sufficient to effect the reverse TCA flux and maintain cellular viability.


Available from: Andrei Osterman, Oct 31, 2014
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Many cancers adopt a metabolism that is characterized by the well-known Warburg effect (aerobic glycolysis). Recently, numerous attempts have been made to treat cancer by targeting one or more gene products involved in this pathway without notable success. This work outlines a transcriptomic approach to identify genes that are highly perturbed in clear cell renal cell carcinoma (CCRCC). We developed a model of the extended Warburg effect and outlined the model using Cytoscape. Following this, gene expression fold changes (FCs) for tumor and adjacent normal tissue from patients with CCRCC (GSE6344) were mapped on to the network. Gene expression values with FCs of greater than two were considered as potential targets for treatment of CCRCC. The Cytoscape network includes glycolysis, gluconeogenesis, the pentose phosphate pathway (PPP), the TCA cycle, the serine/glycine pathway, and partial glutaminolysis and fatty acid synthesis pathways. Gene expression FCs for nine of the 10 CCRCC patients in the GSE6344 data set were consistent with a shift to aerobic glycolysis. Genes involved in glycolysis and the synthesis and transport of lactate were over-expressed, as was the gene that codes for the kinase that inhibits the conversion of pyruvate to acetyl-CoA. Interestingly, genes that code for unique proteins involved in gluconeogenesis were strongly under-expressed as was also the case for the serine/glycine pathway. These latter two results suggest that the role attributed to the M2 isoform of pyruvate kinase (PKM2), frequently the principal isoform of PK present in cancer: i.e. causing a buildup of glucose metabolites that are shunted into branch pathways for synthesis of key biomolecules, may not be operative in CCRCC. The fact that there was no increase in the expression FC of any gene in the PPP is consistent with this hypothesis. Literature protein data generally support the transcriptomic findings. A number of key genes have been identified that could serve as valid targets for anti-cancer pharmaceutical agents. Genes that are highly over-expressed include ENO2, HK2, PFKP, SLC2A3, PDK1, and SLC16A1. Genes that are highly under-expressed include ALDOB, PKLR, PFKFB2, G6PC, PCK1, FBP1, PC, and SUCLG1.
    01/2015; 2(2):151-86.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A functional genomics study revealed that the activity of acetyl-CoA synthetase 2 (ACSS2) contributes to cancer cell growth under low-oxygen and lipid-depleted conditions. Comparative metabolomics and lipidomics demonstrated that acetate is used as a nutritional source by cancer cells in an ACSS2-dependent manner, and supplied a significant fraction of the carbon within the fatty acid and phospholipid pools. ACSS2 expression is upregulated under metabolically stressed conditions and ACSS2 silencing reduced the growth of tumor xenografts. ACSS2 exhibits copy-number gain in human breast tumors, and ACSS2 expression correlates with disease progression. These results signify a critical role for acetate consumption in the production of lipid biomass within the harsh tumor microenvironment. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cancer cell 01/2015; 27(1). DOI:10.1016/j.ccell.2014.12.002 · 23.89 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The study of tumor metabolism has resulted in new understandings of how cancer cells modify metabolic pathways that control cellular energetics to allow increased proliferation and survival. Tumor cells have been shown to alter metabolic pathways involved in glucose, glutamine, and mitochondrial metabolism to generate raw materials needed for rapid cellular proliferation, maintain favorable cellular redox environments, modify cellular epigenetics, and even promote and maintain oncogenic transformation. As a consequence, there has been intense scientific and clinical interest in targeting metabolic alterations that are commonly adopted by tumor cells for therapeutic purposes. In this review, we describe common metabolic alterations seen in tumor cells and discuss how these alterations are being investigated as potential targets for pharmacological intervention in preclinical and clinical settings. We also discuss some of the challenges associated with using tumor metabolism as a therapeutic target in cancer therapy, along with potential avenues to overcome these challenges.
    The Cancer Journal 03/2015; 21(2):62-9. DOI:10.1097/PPO.0000000000000099 · 3.61 Impact Factor