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      Dietary restriction of amino acids for Cancer therapy

      review-article
      Nutrition & Metabolism
      BioMed Central
      Amino acid restriction, Cancer, Lysine, Kwashiorkor, Tryptophan, Arginine, Cachexia

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          Abstract

          Biosyntheses of proteins, nucleotides and fatty acids, are essential for the malignant proliferation and survival of cancer cells. Cumulating research findings show that amino acid restrictions are potential strategies for cancer interventions. Meanwhile, dietary strategies are popular among cancer patients. However, there is still lacking solid rationale to clarify what is the best strategy, why and how it is. Here, integrated analyses and comprehensive summaries for the abundances, signalling and functions of amino acids in proteomes, metabolism, immunity and food compositions, suggest that, intermittent dietary lysine restriction with normal maize as an intermittent staple food for days or weeks, might have the value and potential for cancer prevention or therapy. Moreover, dietary supplements were also discussed for cancer cachexia including dietary immunomodulatory.

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          Most cited references58

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          Sestrin2 is a leucine sensor for the mTORC1 pathway.

          Leucine is a proteogenic amino acid that also regulates many aspects of mammalian physiology, in large part by activating the mTOR complex 1 (mTORC1) protein kinase, a master growth controller. Amino acids signal to mTORC1 through the Rag guanosine triphosphatases (GTPases). Several factors regulate the Rags, including GATOR1, aGTPase-activating protein; GATOR2, a positive regulator of unknown function; and Sestrin2, a GATOR2-interacting protein that inhibits mTORC1 signaling. We find that leucine, but not arginine, disrupts the Sestrin2-GATOR2 interaction by binding to Sestrin2 with a dissociation constant of 20 micromolar, which is the leucine concentration that half-maximally activates mTORC1. The leucine-binding capacity of Sestrin2 is required for leucine to activate mTORC1 in cells. These results indicate that Sestrin2 is a leucine sensor for the mTORC1 pathway.
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            Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion

            The metabolic characteristics of tumors present considerable hurdles to immune cell function and cancer immunotherapy. Using a glutamine antagonist, we metabolically dismantled the immunosuppressive microenvironment of tumors. We demonstrate that glutamine blockade in tumor-bearing mice suppresses oxidative and glycolytic metabolism of cancer cells, leading to decreased hypoxia, acidosis, and nutrient depletion. By contrast, effector T cells responded to glutamine antagonism by markedly up-regulating oxidative metabolism and adopting a long-lived, highly activated phenotype. These divergent changes in cellular metabolism and programming form the basis for potent antitumor responses. Glutamine antagonism therefore exposes a previously undefined difference in metabolic plasticity between cancer cells and effector T cells that can be exploited as a “metabolic checkpoint” for tumor immunotherapy.
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              GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase.

              Indoleamine 2,3 dioxygenase (IDO) catabolizes the amino acid tryptophan. IDO-expressing immunoregulatory dendritic cells (DCs) have been implicated in settings including tumors, autoimmunity, and transplant tolerance. However, the downstream molecular mechanisms by which IDO functions to regulate T cell responses remain unknown. We now show that IDO-expressing plasmacytoid DCs activate the GCN2 kinase pathway in responding T cells. GCN2 is a stress-response kinase that is activated by elevations in uncharged tRNA. T cells with a targeted disruption of GCN2 were not susceptible to IDO-mediated suppression of proliferation in vitro. In vivo, proliferation of GCN2-knockout T cells was not inhibited by IDO-expressing DCs from tumor-draining lymph nodes. IDO induced profound anergy in responding wild-type T cells, but GCN2-knockout cells were refractory to IDO-induced anergy. We hypothesize that GCN2 acts as a molecular sensor in T cells, allowing them to detect and respond to conditions created by IDO.
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                Author and article information

                Contributors
                kjs@zzu.edu.cn
                Journal
                Nutr Metab (Lond)
                Nutr Metab (Lond)
                Nutrition & Metabolism
                BioMed Central (London )
                1743-7075
                14 March 2020
                14 March 2020
                2020
                : 17
                : 20
                Affiliations
                GRID grid.412633.1, Clinical Systems Biology Laboratories, , The First Affiliated Hospital of Zhengzhou University, ; Zhengzhou, 450052 China
                Author information
                https://orcid.org/0000-0002-2603-9718
                Article
                439
                10.1186/s12986-020-00439-x
                7071719
                32190097
                8f304822-b3f7-4c01-a430-88de385cd13d
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.

                History
                : 20 January 2020
                : 6 March 2020
                Categories
                Review
                Custom metadata
                © The Author(s) 2020

                Nutrition & Dietetics
                amino acid restriction,cancer,lysine,kwashiorkor,tryptophan,arginine,cachexia
                Nutrition & Dietetics
                amino acid restriction, cancer, lysine, kwashiorkor, tryptophan, arginine, cachexia

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