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      Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer

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          Abstract

          Cancer cells often require glutamine for growth, thereby distinguishing them from most normal cells. Here we show that PIK3CA mutations reprogram glutamine metabolism by upregulating glutamate pyruvate transaminase 2 (GPT2) in colorectal cancer (CRC) cells, making them more dependent on glutamine. Compared with isogenic wild-type (WT) cells, PIK3CA mutant CRCs convert substantially more glutamine to α-ketoglutarate to replenish the tricarboxylic acid cycle and generate ATP. Mutant p110α upregulates GPT2 gene expression through an AKT-independent, PDK1–RSK2–ATF4 signalling axis. Moreover, aminooxyacetate, which inhibits the enzymatic activity of aminotransferases including GPT2, suppresses xenograft tumour growth of CRCs with PIK3CA mutations, but not with WT PIK3CA. Together, these data establish oncogenic PIK3CA mutations as a cause of glutamine dependency in CRCs and suggest that targeting glutamine metabolism may be an effective approach to treat CRC patients harbouring PIK3CA mutations.

          Abstract

          Cancer cells rely on glutamine to replenish the TCA cycle. Here, the authors show that oncogenic PIK3CA mutations drive this metabolic rewiring in colorectal cancer cells by up-regulating glutamate pyruvate transaminase expression, thus increasing sensitivity to glutamine starvation.

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          Most cited references24

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          The genomic landscapes of human breast and colorectal cancers.

          Human cancer is caused by the accumulation of mutations in oncogenes and tumor suppressor genes. To catalog the genetic changes that occur during tumorigenesis, we isolated DNA from 11 breast and 11 colorectal tumors and determined the sequences of the genes in the Reference Sequence database in these samples. Based on analysis of exons representing 20,857 transcripts from 18,191 genes, we conclude that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene "mountains" and a much larger number of gene "hills" that are mutated at low frequency. We describe statistical and bioinformatic tools that may help identify mutations with a role in tumorigenesis. These results have implications for understanding the nature and heterogeneity of human cancers and for using personal genomics for tumor diagnosis and therapy.
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            Links between metabolism and cancer.

            Chi Dang (2012)
            Metabolism generates oxygen radicals, which contribute to oncogenic mutations. Activated oncogenes and loss of tumor suppressors in turn alter metabolism and induce aerobic glycolysis. Aerobic glycolysis or the Warburg effect links the high rate of glucose fermentation to cancer. Together with glutamine, glucose via glycolysis provides the carbon skeletons, NADPH, and ATP to build new cancer cells, which persist in hypoxia that in turn rewires metabolic pathways for cell growth and survival. Excessive caloric intake is associated with an increased risk for cancers, while caloric restriction is protective, perhaps through clearance of mitochondria or mitophagy, thereby reducing oxidative stress. Hence, the links between metabolism and cancer are multifaceted, spanning from the low incidence of cancer in large mammals with low specific metabolic rates to altered cancer cell metabolism resulting from mutated enzymes or cancer genes.
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              Serial analysis of gene expression.

              The characteristics of an organism are determined by the genes expressed within it. A method was developed, called serial analysis of gene expression (SAGE), that allows the quantitative and simultaneous analysis of a large number of transcripts. To demonstrate this strategy, short diagnostic sequence tags were isolated from pancreas, concatenated, and cloned. Manual sequencing of 1000 tags revealed a gene expression pattern characteristic of pancreatic function. New pancreatic transcripts corresponding to novel tags were identified. SAGE should provide a broadly applicable means for the quantitative cataloging and comparison of expressed genes in a variety of normal, developmental, and disease states.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group
                2041-1723
                20 June 2016
                2016
                : 7
                : 11971
                Affiliations
                [1 ]Department of Genetics and Genome Sciences, Case Western Reserve University , 10900 Euclid Avenue, Cleveland, Ohio 44106, USA
                [2 ]Case Comprehensive Cancer Center, Case Western Reserve University , 10900 Euclid Avenue, Cleveland, Ohio 44106, USA
                [3 ]Ludwig Center and Howard Hughes Medical Institute, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins , Baltimore, Maryland 21231, USA
                [4 ]Department of Molecular Cell Biology, The Weizmann Institute of Science , Rehovot 76100, Israel
                [5 ]Department of Nutrition, Case Western Reserve University , 10900 Euclid Avenue, Cleveland, Ohio 44106, USA
                [6 ]Department of Pharmacology, School of Medicine, Case Western Reserve University , 10900 Euclid Avenue, Cleveland, Ohio 44106, USA
                [7 ]Department of Biochemistry and Molecular Biology, Wannan Medical College , Wuhu 241000, China
                [8 ]Department of Pharmacognosy, School of Pharmacy, Third Military Medical University , Chongqing 400038, China
                [9 ]Department of Pharmacy, Suzhou Health College , Suzhou, Jiangsu 215009, China
                [10 ]Hathaway Brown School , 19600 North Park Boulevard, Shaker Heights, Ohio 44122, USA
                [11 ]Department of Medicine, University Hospitals Case Medical Center, Case Western Reserve University , 10900 Euclid Avenue, Cleveland, Ohio 44106, USA
                [12 ]Department of Chemistry, Cleveland State University , 2121 Euclid Avenue, Cleveland, Ohio 44115, USA
                [13 ]Department of Pathology, University Hospitals Case Medical Center, Case Western Reserve University , 10900 Euclid Avenue, Cleveland, Ohio 44106, USA
                Author notes
                [*]

                These authors contributed equally to this work.

                [†]

                Present address: Division of Cellular & Molecular Research, National Cancer Center Singapore, Singapore 169610, Singapore.

                Article
                ncomms11971
                10.1038/ncomms11971
                4915131
                27321283
                34e7a36f-c0a5-4afb-b43c-7301a54ca5bc
                Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 11 January 2016
                : 17 May 2016
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