Metabolite sensing and signaling in cancer

Abstract

Metabolites are not only substrates in metabolic reactions, but also signaling molecules controlling a wide range of cellular processes. Discovery of the oncometabolite 2-hydroxyglutarate provides an important link between metabolic dysfunction and cancer, unveiling the signaling function of metabolites in regulating epigenetic and epitranscriptomic modifications, genome integrity, and signal transduction. It is now known that cancer cells remodel their metabolic network to support biogenesis, caused by or resulting in the dysregulation of various metabolites. Cancer cells can sense alterations in metabolic intermediates to better coordinate multiple biological processes and enhance cell metabolism. Recent studies have demonstrated that metabolite signaling is involved in the regulation of malignant transformation, cell proliferation, epithelial-to-mesenchymal transition, differentiation blockade, and cancer stemness. Additionally, intercellular metabolite signaling modulates inflammatory response and immunosurveillance in the tumor microenvironment. Here, we review recent advances in cancer-associated metabolite signaling. An in depth understanding of metabolite signaling will provide new opportunities for the development of therapeutic interventions that target cancer. Metabolites are not only substrates in metabolic reactions, but also signaling molecules controlling a wide range of cellular processes. Discovery of the oncometabolite 2-hydroxyglutarate provides an important link between metabolic dysfunction and cancer, unveiling the signaling function of metabolites in regulating epigenetic and epitranscriptomic modifications, genome integrity, and signal transduction. It is now known that cancer cells remodel their metabolic network to support biogenesis, caused by or resulting in the dysregulation of various metabolites. Cancer cells can sense alterations in metabolic intermediates to better coordinate multiple biological processes and enhance cell metabolism. Recent studies have demonstrated that metabolite signaling is involved in the regulation of malignant transformation, cell proliferation, epithelial-to-mesenchymal transition, differentiation blockade, and cancer stemness. Additionally, intercellular metabolite signaling modulates inflammatory response and immunosurveillance in the tumor microenvironment. Here, we review recent advances in cancer-associated metabolite signaling. An in depth understanding of metabolite signaling will provide new opportunities for the development of therapeutic interventions that target cancer. For decades, metabolites have been perceived as substrates of enzymes and/or regulators of their biosynthetic pathways (1Wang K. Jiang J. Lei Y. Zhou S. Wei Y. Huang C. Targeting metabolic-redox circuits for cancer therapy.Trends Biochem. Sci. 2019; 44 (30679131): 401-41410.1016/j.tibs.2019.01.001Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 2Wang Y. Bai C. Ruan Y. Liu M. Chu Q. Qiu L. Yang C. Li B. Coordinative metabolism of glutamine carbon and nitrogen in proliferating cancer cells under hypoxia.Nat. Commun. 2019; 10 (30643150): 20110.1038/s41467-018-08033-9Crossref PubMed Scopus (39) Google Scholar, 3Wegner A. Meiser J. Weindl D. Hiller K. How metabolites modulate metabolic flux.Curr. Opin. Biotechnol. 2015; 34 (25461507): 16-2210.1016/j.copbio.2014.11.008Crossref PubMed Scopus (50) Google Scholar). Recently, increasing evidence has suggested that metabolites are signaling molecules (4Wang Y.P. Lei Q.Y. Metabolite sensing and signaling in cell metabolism.Signal Transduct. Target. Ther. 2018; 3 (30416760): 3010.1038/s41392-018-0024-7Crossref PubMed Scopus (40) Google Scholar). Alterations in specific metabolites have been shown to modulate the activity of macromolecules. In this scenario, metabolites are emerging as signaling molecules that control biological processes, including epigenetic modification, signal transduction, and intercellular communication. Nutrients are digested into various intracellular and extracellular metabolites, which are produced via intermediary metabolism. Cells actively sense these metabolites to coordinate metabolic and nonmetabolic processes. These sensing and signaling mechanisms are core processes for the interaction between cellular metabolism and nonmetabolic processes. Notably, deregulation of metabolite signaling is implicated in numerous human diseases, including cancer. For example, 5′-adenosine monophosphate-activated protein kinase and mTOR complex 1 (mTORC1) are important energy/nutrient sensors that regulate energy production, protein synthesis, and autophagic processes to maintain metabolic homeostasis. Dysregulation of 5′-adenosine monophosphate-activated protein kinase and mTORC1 signaling leads to aberrant glucose and amino acids sensing in cancer cells, which have been reviewed elsewhere (5González A. Hall M.N. Nutrient sensing and TOR signaling in yeast and mammals.EMBO J. 2017; 36 (28096180): 397-40810.15252/embj.201696010Crossref PubMed Scopus (278) Google Scholar, 6Garcia D. Shaw R.J. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance.Mol. Cell. 2017; 66 (28622524): 789-80010.1016/j.molcel.2017.05.032Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar). Although metabolite signaling plays a fundamental role in interconnecting cellular metabolism with signaling events, the diversity of metabolites in their spatial structure and chemical properties precludes generic techniques that can be used to elucidate their biological function in cellular signaling. Consequently, the function of metabolites as signaling molecules has remained largely unexplored until recently. The discovery that the oncometabolite 2-hydroxyglutarate (2HG), generated by mutant isocitrate dehydrogenase 1 and 2 (IDH1/2), has functions beyond cell metabolism in cancer initiation and progression has placed renewed emphasis on this field. Besides 2HG, a growing number of metabolites have been shown to modulate various signaling pathways. Here, we review the recent progress in our understanding of how metabolite signaling interacts with diverse biological processes to regulate malignant transformation and remodel the tumor microenvironment. To sustain malignant growth, cancer cells gauge nutrient availability to coordinate cellular metabolism. Deregulation of metabolic pathways, also known as metabolic reprogramming, is a key feature of cancer cells. Reprogrammed metabolic pathways reshape the cancer metabolome (i.e. the abundance of metabolites), which allows cancer cells to modulate oncogenic signaling with specific metabolites. The role of 2HG as a signaling molecule did not receive much attention until the discovery of cancer-driving mutations in IDHs. IDH1 and IDH2 mutations occur on specific residues in the catalytic center, conferring a new catalytic property to IDH, generating 2HG (7Dang L. White D.W. Gross S. Bennett B.D. Bittinger M.A. Driggers E.M. Fantin V.R. Jang H.G. Jin S. Keenan M.C. Marks K.M. Prins R.M. Ward P.S. Yen K.E. Liau L.M. et al.Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.Nature. 2009; 462 (19935646): 739-74410.1038/nature08617Crossref PubMed Scopus (2252) Google Scholar). 2HG is classified as an oncometabolite because mutated IDH1/2 can trigger malignant transformation, leading to the development of cancers such as myeloid leukemia, chondrosarcoma, and glioma (8Waitkus M.S. Diplas B.H. Yan H. Biological role and therapeutic potential of IDH mutations in cancer.Cancer Cell. 2018; 34 (29805076): 186-19510.1016/j.ccell.2018.04.011Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). Additionally, 2HG can be generated by malate dehydrogenase, lactate dehydrogenase (LDH), and phosphoglycerate dehydrogenase through their catalytic promiscuity. 2-Hydroxyglutarate dehydrogenase counteracts these enzymes by clearing cellular 2HG at a low efficiency (9Fan J. Teng X. Liu L. Mattaini K.R. Looper R.E. Vander Heiden M.G. Rabinowitz J.D. Human phosphoglycerate dehydrogenase produces the oncometabolite d-2-hydroxyglutarate.ACS Chem. Biol. 2015; 10 (25406093): 510-51610.1021/cb500683cCrossref PubMed Scopus (106) Google Scholar, 10Intlekofer A.M. Dematteo R.G. Venneti S. Finley L.W. Lu C. Judkins A.R. Rustenburg A.S. Grinaway P.B. Chodera J.D. Cross J.R. Thompson C.B. Hypoxia induces production of l-2-hydroxyglutarate.Cell Metab. 2015; 22 (26212717): 304-31110.1016/j.cmet.2015.06.023Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar). 2HG acts as a signaling metabolite that regulates a wide range of cellular processes (Fig. 1). It contributes to metabolic remodeling by inhibiting multiple metabolic enzymes, including ATP synthase (11Fu X. Chin R.M. Vergnes L. Hwang H. Deng G. Xing Y. Pai M.Y. Li S. Ta L. Fazlollahi F. Chen C. Prins R.M. Teitell M.A. Nathanson D.A. Lai A. et al.2-Hydroxyglutarate inhibits ATP synthase and mTOR signaling.Cell Metab. 2015; 22 (26190651): 508-51510.1016/j.cmet.2015.06.009Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar), and by deregulating the tricarboxylic acid (TCA) cycle (12Reitman Z.J. Jin G. Karoly E.D. Spasojevic I. Yang J. Kinzler K.W. He Y. Bigner D.D. Vogelstein B. Yan H. Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome.Proc. Natl. Acad. Sci. U. S. A. 2011; 108 (21289278): 3270-327510.1073/pnas.1019393108Crossref PubMed Scopus (318) Google Scholar) in the mitochondria. In addition, 2HG disrupts redox metabolism, which is a key factor involved in tumor progression (1Wang K. Jiang J. Lei Y. Zhou S. Wei Y. Huang C. Targeting metabolic-redox circuits for cancer therapy.Trends Biochem. Sci. 2019; 44 (30679131): 401-41410.1016/j.tibs.2019.01.001Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). 2HG acts as a structural analog of α-ketoglutarate (α-KG), an amino group acceptor in transamination reactions, resulting in suppression of branched-chain aminotransferase (BCAT) and impairment of GSH production to disrupt the redox balance in glioma (13McBrayer S.K. Mayers J.R. DiNatale D.D. J. K. et by 2-hydroxyglutarate and redox in 2018; Full Text Full Text PDF PubMed Scopus Google Scholar). 2HG can also as a of epigenetic and epitranscriptomic 2HG inhibits including enzymes, and and protein leading to a of and factor tumor 1 to specific to myeloid 2HG disrupts the signaling to the development of myeloid cancers Lu C. Ward P.S. J. A. Li Y. A. M.S. K. Liu et IDH1 and IDH2 mutations in a disrupt and Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. M. Chen X. Chen L. Y. L. Yang H. S. H. B. D. Y. to regulate target and cell Cell. 2015; Full Text Full Text PDF PubMed Scopus Google Scholar). In addition, 2HG to enhance in glioma C. Ward P.S. D. S. A. K.E. et and in a to cell PubMed Scopus Google Scholar, L. Li Yang M. M.A. R.J. et oncometabolite 2-hydroxyglutarate inhibits 2011; PubMed Scopus Google Scholar). 2HG can also activity to of controlling the of protein L. Li C. S. M. Y. Deng X. Y. X. C. M. J. Q. D. et activity by 2018; Full Text Full Text PDF PubMed Scopus Google Scholar). 2HG can also modulate oncogenic signaling pathways. to 2HG protein to mTORC1 signaling in (11Fu X. Chin R.M. Vergnes L. Hwang H. Deng G. Xing Y. Pai M.Y. Li S. Ta L. Fazlollahi F. Chen C. Prins R.M. Teitell M.A. Nathanson D.A. Lai A. et al.2-Hydroxyglutarate inhibits ATP synthase and mTOR signaling.Cell Metab. 2015; 22 (26190651): 508-51510.1016/j.cmet.2015.06.009Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar). increasing the cellular 2HG also extracellular protein kinase of and activity in cells. 2HG signaling the of and that will provide support for cell and Lai Yen The oncometabolite for myeloid PubMed Scopus Google Scholar). 2HG can also signal and of 1 signaling and the production of 10 which in cell and immunosurveillance in glioma G. D.A. S. K.M. P.B. C. C. H. dehydrogenase mutations and cell in 2017; PubMed Scopus Google Scholar). 2HG which the of factor the transformation of mutant IDH S. G. Lu G. S. U. Gross S. J. S. Looper R.G. et by the of 2-hydroxyglutarate to PubMed Scopus Google Scholar). 2HG signaling leads to aberrant activity of the that genome 2HG a group of enzymes that F. K. Q. Li D. and the enzymes under 2017; PubMed Scopus Google Scholar). 2HG signaling also disrupts the activity of enzymes through an resulting in in glioma K.R. Bai H. Liu Y. Y. K. et al.2-Hydroxyglutarate produced by IDH mutations and induces 2017; PubMed Scopus Google Scholar). in cells a for glioma with as by the of glioma cells to K.R. Bai H. Liu Y. Y. K. et al.2-Hydroxyglutarate produced by IDH mutations and induces 2017; PubMed Scopus Google Scholar, J. S. L. J. D. Y. inhibits enzymes and IDH mutant cells to 2015; Full Text Full Text PDF PubMed Scopus Google Scholar). The of 2HG in and to a new for cancer cells to Notably, 2HG signaling with oncogenic signaling pathways to cancer such as mutant and the activity of mutant IDH to enhance 2HG signaling D. S. M. Li Y. H. M. X. Y. Liu S. J. Jin L. et and isocitrate dehydrogenase 1 mechanisms kinase in cancer.Cancer 2019; PubMed Scopus Google Scholar, A. M. Zhou M. Karoly E.D. K. S. D. et of 2-hydroxyglutarate is with cancer PubMed Scopus Google Scholar), that of these cancer in with chemical of mutated IDH, be Cancer cells can sense and the of a wide of metabolites to and including metabolites of carbon metabolism, amino and (Fig. carbon metabolism glucose and produces not only energy but also a of metabolic intermediates to the biosynthetic of cancer cells. these metabolic intermediates to be signaling molecules that control and and the cycle to glucose and ATP production M. Yan Wei L.M. Lu Y.P. Lei Q.Y. to regulate glucose metabolism and is in 2018; Full Text Full Text PDF PubMed Scopus Google Scholar), but in Cells to enhance energy production the X. F. Li Chen C.B. Yang Jiang Yan D. Y. Liu Y. Chen J. et functions as an epigenetic metabolite to under hypoxia.Nat. Commun. PubMed Scopus Google Scholar), the cycle is signaling is a that the of the efficiency of regulation is which of new and cells have a the cells an lactate an of Cells sense the of lactate through 3 protein and a response S. K.M. M. Jang Yang H. et response to 2015; Full Text Full Text PDF PubMed Scopus Google Scholar). to resulting in the of signaling and of S. K.M. M. Jang Yang H. et response to 2015; Full Text Full Text PDF PubMed Scopus Google Scholar). In cancer cells, lactate in the leading to of lactate signaling. the for lactate production, lactate dehydrogenase is involved in a by which metabolites in this role on a catalytic Cancer cells are by transformation, in response to which to the activity is produces and signaling by of signaling is in redox balance in human cancer Y. Liu Y. K. H. Liu X. Zhou S. Lu Yang C. Zhou L. Y.P. et lactate dehydrogenase to produce for tumor Commun. 2018; PubMed Scopus Google Scholar). signaling with to cell in of cancer. The cycle also produces a of signaling metabolites that be of to cancer D. Lei J. He Lei Q.Y. Y.P. of glucose sensing with 2018; PubMed Scopus Google Scholar, Y. Q. J. Zhou He J. J. Chen Y. J. Y. Wei B. Q. Yang J. Y. et signaling protein and Cell. 2019; Full Text Full Text PDF PubMed Scopus Google Scholar). of which is in and cell cancer, leads to the of in human cancer cells. is a structural analog to and in inhibits and of a this the of that the epithelial-to-mesenchymal and cell transformation M. V.R. A.S. M.G. S. S. H. et is an epigenetic that epithelial-to-mesenchymal PubMed Scopus Google Scholar). Notably, a of shown to G. M. S. F. C. A. A. G. G. in and 2017; PubMed Scopus Google Scholar), a link between signaling and cellular is not only the for energy production but also a of the a glucose is to 1 and cancer cells have been shown to to and the processes of and X. Liu Chu H. H. Wei X. H. H. J. Li G. Yang and cancer 2019; PubMed Scopus Google Scholar). are of energy and the of and intracellular but have also been to regulate multiple signaling Cancer cells sense the abundance of acids by protein and acid to to the activity of L. acids regulate acid and by protein Commun. 2015; PubMed Scopus Google Scholar). plays a role by the of involved in cell and with tumor in a of cancer L. acids regulate acid and by protein Commun. 2015; PubMed Scopus Google Scholar). are a specific of which can can be by the which in will the of the including and in the of the and the of intracellular Additionally, can the to signaling and malignant transformation by factor and in tumor cells L. D. A. K. Yang D. I. metabolites regulate of via 2015; Full Text Full Text PDF PubMed Scopus Google Scholar). The of cellular be a metabolic of cell and is by such as the of feature allows cells to be into Cancer cells are to be the of and These cells metabolic to of a better understanding of the metabolic of can metabolite signaling pathways that sustain A. D. H. A. et of dehydrogenase differentiation in myeloid Full Text Full Text PDF PubMed Scopus Google Scholar, D. D. A. Y. A. D. mTORC1 regulation in 2017; PubMed Scopus Google Scholar, S. C. L. S. H. A. A. K. K. S. H. D. M. et dehydrogenase differentiation and is in the of myeloid 2019; PubMed Scopus Google Scholar). cancer cells have of and the of is to the of these cells. of signaling and activity of J. S. J. X. Y. D. is a metabolic and therapeutic target of cancer Cell. 2017; Full Text Full Text PDF PubMed Scopus Google Scholar). as a target in is structural of that metabolism is to cell 3 a remodeling regulates The of induces of and to cells, resulting in of B. X. J. A.M. M.G. D.A. remodeling and availability regulate and Cell. 2018; 22 Full Text Full Text PDF PubMed Scopus Google Scholar). Cancer cells of amino acids to sustain the and for tumor cells have an for leading to glutamine in the microenvironment. a cancer cells sense glutamine and of amino acids glutamine cancer cells sense glutamine and and kinase signaling to extracellular through and support cancer metabolism Y. M. B. C. signaling regulates glutamine Cell. 2019; Full Text Full Text PDF PubMed Scopus Google Scholar). The intermediates of amino acids metabolism have been shown to with cellular signaling. signaling plays a key role in cell and of signaling has been in various of cancer. acid a in interacts with and signaling J. A. regulation of signaling by the metabolite 2015; PubMed Scopus Google Scholar). metabolism be to signaling and tumor Additionally, dysfunction of the has a signaling role in The metabolism is in such as in the of structural with which is a in inhibits protein by resulting in activity and of A. D.A. K. J. G. M. S. Y. Liu Y. et metabolism in cancers leads to on PubMed Scopus Google Scholar, J.R. J. A. F. M. C. et on the in cancer PubMed Scopus Google Scholar). Although the biological with the of cancer cells. acids are also regulators of cancer cells. For example, branched-chain amino acids which are for cell growth, to have an link with cell and cancer stemness. to or the of cells M. H. S. amino acid for cell amino acid 2018; Full Text Full Text PDF PubMed Scopus Google Scholar). branched-chain aminotransferase 1 which is the for in cells. abundance to differentiation and the of cells, as of the differentiation of myeloid cells A. M. M. J. F. D. A. A.S. Cancer progression by metabolism in myeloid 2017; PubMed Scopus Google Scholar). an amino group to and intracellular Consequently, the activity of enzymes is to S. M. J. C. L. G. Y. A. C. A. M. M. et in cells leading to 2017; PubMed Scopus Google Scholar). the of is for the progression of cancer M. D. J. Lei Y. Liu Y. L. Y.P. Lu Chen Z.J. et is for development of Biol. 22 PubMed Scopus Google Scholar). the of signaling and how regulate cancer progression to be Cancer cells their of and at in by the of and can as a signaling molecule that cell In the of myeloid cells are at an to a differentiation D. M.S. Y. K. F. M. M. D. A. D. A. et cellular of the in and 2019; Full Text Full Text PDF PubMed Scopus Google Scholar). have dehydrogenase, an involved in synthesis, as for this differentiation dehydrogenase is a key in synthesis, metabolites have a signaling function to control cell in of the signaling to the metabolic of the differentiation in A. D. H. A. et of dehydrogenase differentiation in myeloid Full Text Full Text PDF PubMed Scopus Google Scholar). The tumor is of cancer cells and cancer-associated as as and D. Y. Liu J. X. J. S. Zhou J. of cancer-associated by 2015; 10 Full Text Full Text PDF PubMed Scopus Google Scholar). To sustain proliferation, tumor cells for in intercellular and metabolic to reshape the metabolic of the extracellular the activity of cells is by cancer metabolism to an of cancer progression (Fig. cells of glucose and the cells of a in these cells is and a is known to the activity of which the into the controlling in the factor factor of cells to the of target and cell response J.D. M. Liu X. G. G. E.D. S. et is a metabolic of cell 2015; Full Text Full Text PDF PubMed Scopus Google Scholar). in the function of cells, which have glucose metabolism to be to signaling the tumor the of tumor cells in lactate and of the microenvironment. is a signaling metabolite that which response signaling is to support production and signaling is also involved in cancer to the signaling protein and interaction with The suppression of signaling and cancer progression G. H. F. J. Y. Chen Y. Lu Y. H. F. C. Jin G. L. et is a of signaling by 2019; Full Text Full Text PDF PubMed Scopus Google Scholar). acids are important regulators of and a key signaling metabolite in tumor can be by the and which will signaling plays a role in and F. M. I. S. L. D. M. M. C. B. et of the human 2011; PubMed Scopus Google Scholar, I. metabolites in and 2017; PubMed Scopus Google Scholar). cells can into cells that response such as 1 cells that are involved in the of tumor cells, or into cells that cell differentiation can be by tumor metabolism. For glutamine metabolism is a metabolic of cell differentiation as can cell Additionally, cells can into cells in the of glutamine or into cells in the of this amino the of the factor which differentiation D. X. M. G. L. C. S. C. J. et α-ketoglutarate production regulates the balance between 1 cell and cell 2015; PubMed Scopus Google Scholar). of to or modulates mTORC1 signaling to cells cell cancer cells for glutamine in the tumor a that glutamine for cells. The will to immunosurveillance G. A. D. K. R.J. Li G. Y. et regulation of and cell differentiation by 2018; Full Text Full Text PDF PubMed Scopus Google Scholar). acids and are also involved in the regulation of inflammatory and as key tumor cells with their cells. Notably, cancer-associated are important cellular of the tumor that are for and signaling. by cancer-associated a wide of such as amino and cycle metabolites, to cancer cells nutrient H. Yang L. J. A. H. S. L. D. et modulate cancer cell PubMed Scopus Google Scholar). metabolite signaling is also involved in the development of which is a factor for cancer. is by cell and cells of extracellular with of and A. H. signaling of inflammatory extracellular Full Text Full Text PDF PubMed Scopus Google Scholar). the that can tumor factor signaling and cell with to the of and and enhance A. H. signaling of inflammatory extracellular Full Text Full Text PDF PubMed Scopus Google Scholar). to cancer, of is involved in the remodeling of the cancer microenvironment. acids are also metabolites in the tumor microenvironment. Human cells produce acids as the metabolites of metabolism. The link between acids and cancer has been of acids and in cancer and with PubMed Scopus Google Scholar), with the signaling function of acids in energy metabolism, and cancer. acids have been shown to on the and cell acids to and acid which regulate metabolism and energy production by the or activity of metabolic enzymes acid signaling in metabolic and 66 PubMed Scopus Google Scholar). In acids effects in cancer. In cells, acids trigger the of to enhance immunosurveillance by increasing cells C. M. B. Q. Q. M. D. M. S. et acid metabolism regulates cancer via 2018; PubMed Scopus Google Scholar). The is a of metabolites the human and is also a of metabolite signaling. Metabolites generated by are important signaling molecules in cells and cancer cells in the metabolites, including and as signaling molecules to the and cancer M. D. L. G. A. Y. M. H. A. A. et metabolites the by regulating 2015; Full Text Full Text PDF PubMed Scopus Google Scholar). is an important signaling metabolite in cancer. with in the and The of in human cells tumor K. of the human to sense 2015; PubMed Scopus Google Scholar). Metabolite signaling is to be a not only to metabolic remodeling of cancer but also cellular metabolism with signaling the signaling of metabolites is how cells sense these metabolites and their are in It is important to that the abundance of metabolites is and largely on nutrient and cell of cancer cells under or cancer cells with the discovery of new signaling of metabolites. metabolites are known to in a cells H. C.B. R.J. C. B. Hiller K. R.G. R.G. et for metabolite Opin. Biotechnol. 2015; 34 PubMed Scopus Google Scholar). the metabolite have signaling in cellular Although we have of intracellular metabolite this between cell and largely tumor cells are known to to cancer and understanding of intercellular and metabolite signaling also to elucidate in a such as and The development of new or to our understanding of metabolite signaling in cancer. The signaling role of a metabolite is largely on interaction with macromolecules. for discovery of are such as that the and discovery of metabolites on key signaling pathways in cancer. therapeutic of metabolite signaling for in cancer. For example, chemical of mutant IDH have been in the of leukemia, and we that discovery of of metabolites and their will provide opportunities for the development of new of cancer. of the Lei for this target of mTOR complex 1 branched-chain amino acids aminotransferase and protein 2-hydroxyglutarate isocitrate dehydrogenase tricarboxylic acid α-ketoglutarate tumor 1 factor lactate dehydrogenase of acids factor cancer cell protein kinase acid branched-chain amino acids myeloid 1

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