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      Grasping for aspartate in tumour metabolism

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      Nature Cell Biology
      Springer Nature

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          Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor

          Cellular amino acid uptake is critical for mTOR complex 1 (mTORC1) activation and cell proliferation. However, the regulation of amino acid uptake is not well-understood. Here we describe a role for asparagine as an amino acid exchange factor: intracellular asparagine exchanges with extracellular amino acids. Through asparagine synthetase knockdown and altering of media asparagine concentrations, we show that intracellular asparagine levels regulate uptake of amino acids, especially serine, arginine and histidine. Through its exchange factor role, asparagine regulates mTORC1 activity and protein synthesis. In addition, we show that asparagine regulation of serine uptake influences serine metabolism and nucleotide synthesis, suggesting that asparagine is involved in coordinating protein and nucleotide synthesis. Finally, we show that maintenance of intracellular asparagine levels is critical for cancer cell growth. Collectively, our results indicate that asparagine is an important regulator of cancer cell amino acid homeostasis, anabolic metabolism and proliferation.
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            Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumors

            SUMMARY As oxygen is essential for many metabolic pathways, tumor hypoxia may impair cancer cell proliferation (1–4). However, the limiting metabolites for proliferation under hypoxia and in tumors are unknown. Here, we assessed proliferation of a collection of cancer cells upon inhibition of the mitochondrial electron transport chain (ETC), a major metabolic pathway requiring molecular oxygen (5). Sensitivity to ETC inhibition varied across cell lines, and subsequent metabolomic analysis uncovered aspartate availability as a major determinant of sensitivity. Cell lines least sensitive to ETC inhibition maintain aspartate levels by importing it through an aspartate/glutamate transporter, SLC1A3. Genetic or pharmacologic modulation of SLC1A3 activity markedly altered cancer cell sensitivity to ETC inhibitors. Interestingly, aspartate levels also decrease under low oxygen, and increasing aspartate import by SLC1A3 provides a competitive advantage to cancer cells at low oxygen levels and in tumor xenografts. Finally, aspartate levels in primary human tumors negatively correlate with the expression of hypoxia markers, suggesting that tumor hypoxia is sufficient to inhibit ETC and, consequently, aspartate synthesis in vivo. Therefore, aspartate may be a limiting metabolite for tumor growth and aspartate availability could be targeted for cancer therapy.
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              Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion.

              Many cancer cells consume large quantities of glutamine to maintain TCA cycle anaplerosis and support cell survival. It was therefore surprising when RNAi screening revealed that suppression of citrate synthase (CS), the first TCA cycle enzyme, prevented glutamine-withdrawal-induced apoptosis. CS suppression reduced TCA cycle activity and diverted oxaloacetate, the substrate of CS, into production of the nonessential amino acids aspartate and asparagine. We found that asparagine was necessary and sufficient to suppress glutamine-withdrawal-induced apoptosis without restoring the levels of other nonessential amino acids or TCA cycle intermediates. In complete medium, tumor cells exhibiting high rates of glutamine consumption underwent rapid apoptosis when glutamine-dependent asparagine synthesis was suppressed, and expression of asparagine synthetase was statistically correlated with poor prognosis in human tumors. Coupled with the success of L-asparaginase as a therapy for childhood leukemia, the data suggest that intracellular asparagine is a critical suppressor of apoptosis in many human tumors.
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                Author and article information

                Journal
                Nature Cell Biology
                Nat Cell Biol
                Springer Nature
                1465-7392
                1476-4679
                June 25 2018
                Article
                10.1038/s41556-018-0137-9
                29941932
                721a6363-3dd9-4258-af9b-e031c3ea0464
                © 2018

                http://www.springer.com/tdm

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