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Review

The Crucial Roles of Intermediate Metabolites in Cancer

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Pages 6291-6307 | Published online: 10 Aug 2021

References

  • CairnsRA, HarrisIS, MakTW. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011;11(2):85–95. doi:10.1038/nrc298121258394
  • LauAN, Vander HeidenMG. Metabolism in the tumor microenvironment. Ann Rev Cancer Biol. 2020;4(1):17–40. doi:10.1146/annurev-cancerbio-030419-033333
  • PhanLM, YeungSC, LeeMH. Cancer metabolic reprogramming: importance, main features, and potentials for precise targeted anti-cancer therapies. Cancer Biol Med. 2014;11(1):1–19.24738035
  • YoshidaGJ. Metabolic reprogramming: the emerging concept and associated therapeutic strategies. J Exp Clin Cancer Res. 2015;34(1):111. doi:10.1186/s13046-015-0221-y26445347
  • SullivanLB, GuiDY, Vander HeidenMG. Altered metabolite levels in cancer: implications for tumour biology and cancer therapy. Nat Rev Cancer. 2016;16(11):680–693. doi:10.1038/nrc.2016.8527658530
  • GilliesRJ, RobeyI, GatenbyRA. Causes and consequences of increased glucose metabolism of cancers. J Nucl Med. 2008;49(Suppl 2):24s–42s. doi:10.2967/jnumed.107.04725818523064
  • KingA, SelakMA, GottliebE. Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene. 2006;25(34):4675–4682. doi:10.1038/sj.onc.120959416892081
  • WardPS, PatelJ, WiseDR, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17(3):225–234. doi:10.1016/j.ccr.2010.01.02020171147
  • YangM, SogaT, PollardPJ. Oncometabolites: linking altered metabolism with cancer. J Clin Invest. 2013;123(9):3652–3658. doi:10.1172/JCI6722823999438
  • NalbantogluS, KaradagA. Metabolomics bridging proteomics along metabolites/oncometabolites and protein modifications: paving the way toward integrative multiomics. J Pharm Biomed Anal. 2021;199:114031.33857836
  • KinnairdA, ZhaoS, WellenKE, MichelakisED. Metabolic control of epigenetics in cancer. Nat Rev Cancer. 2016;16(11):694–707. doi:10.1038/nrc.2016.8227634449
  • StramAR, PayneRM. Post-translational modifications in mitochondria: protein signaling in the powerhouse. Cell Mol Life Sci. 2016;73(21):4063–4073. doi:10.1007/s00018-016-2280-427233499
  • WangYP, LeiQY. Metabolite sensing and signaling in cell metabolism. Signal Transduct Target Ther. 2018;3(1):30. doi:10.1038/s41392-018-0024-730416760
  • AlfaroukKO, VerduzcoD, RauchC, et al. Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question. Oncoscience. 2014;1(12):777–802. doi:10.18632/oncoscience.10925621294
  • MoelleringRE, CravattBF. Functional lysine modification by an intrinsically reactive primary glycolytic metabolite. Science. 2013;341(6145):549–553. doi:10.1126/science.123832723908237
  • OslundRC, SuX, HaugbroM, et al. Bisphosphoglycerate mutase controls serine pathway flux via 3-phosphoglycerate. Nat Chem Biol. 2017;13(10):1081–1087. doi:10.1038/nchembio.245328805803
  • HitosugiT, ZhouL, ElfS, et al. Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. Cancer Cell. 2012;22(5):585–600. doi:10.1016/j.ccr.2012.09.02023153533
  • HoPC, BihuniakJD, MacintyreAN, et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell. 2015;162(6):1217–1228. doi:10.1016/j.cell.2015.08.01226321681
  • Moreno-FeliciJ, HyroššováP, AragóM, et al. Phosphoenolpyruvate from glycolysis and PEPCK regulate cancer cell fate by altering cytosolic Ca(2). Cells. 2019;9(1):18. doi:10.3390/cells9010018
  • San-MillánI, BrooksGA. Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg effect. Carcinogenesis. 2017;38(2):119–133.27993896
  • IppolitoL, MorandiA, GiannoniE, ChiarugiP. Lactate: a metabolic driver in the tumour landscape. Trends Biochem Sci. 2019;44(2):153–166. doi:10.1016/j.tibs.2018.10.01130473428
  • De SaedeleerCJ, CopettiT, PorporatoPE, VerraxJ, FeronO, SonveauxP. Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells. PLoS One. 2012;7(10):e46571. doi:10.1371/journal.pone.004657123082126
  • VégranF, BoidotR, MichielsC, SonveauxP, FeronO. Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-κB/IL-8 pathway that drives tumor angiogenesis. Cancer Res. 2011;71(7):2550–2560. doi:10.1158/0008-5472.CAN-10-282821300765
  • LeeDC, SohnHA, ParkZY, et al. A lactate-induced response to hypoxia. Cell. 2015;161(3):595–609. doi:10.1016/j.cell.2015.03.01125892225
  • ColegioOR, ChuNQ, SzaboAL, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 2014;513(7519):559–563. doi:10.1038/nature1349025043024
  • KesMMG, Van den BosscheJ, GriffioenAW, HuijbersEJM. Oncometabolites lactate and succinate drive pro-angiogenic macrophage response in tumors. Biochim Biophys Acta Rev Cancer. 2020;1874(2):188427. doi:10.1016/j.bbcan.2020.18842732961257
  • MuX, ShiW, XuY, et al. Tumor-derived lactate induces M2 macrophage polarization via the activation of the ERK/STAT3 signaling pathway in breast cancer. Cell Cycle. 2018;17(4):428–438. doi:10.1080/15384101.2018.144430529468929
  • RolandCL, ArumugamT, DengD, et al. Cell surface lactate receptor GPR81 is crucial for cancer cell survival. Cancer Res. 2014;74(18):5301–5310. doi:10.1158/0008-5472.CAN-14-031924928781
  • FengJ, YangH, ZhangY, et al. Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells. Oncogene. 2017;36(42):5829–5839. doi:10.1038/onc.2017.18828604752
  • BrownTP, GanapathyV. Lactate/GPR81 signaling and proton motive force in cancer: role in angiogenesis, immune escape, nutrition, and Warburg phenomenon. Pharmacol Ther. 2020;206:107451. doi:10.1016/j.pharmthera.2019.10745131836453
  • YangK, XuJ, FanM, et al. Lactate suppresses macrophage pro-inflammatory response to LPS stimulation by inhibition of YAP and NF-κB activation via GPR81-mediated signaling. Front Immunol. 2020;11:587913. doi:10.3389/fimmu.2020.58791333123172
  • ZhangW, WangG, XuZG, et al. Lactate is a natural suppressor of RLR signaling by targeting MAVS. Cell. 2019;178(1):176–189.e115. doi:10.1016/j.cell.2019.05.00331155231
  • LathamT, MackayL, SproulD, et al. Lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression. Nucleic Acids Res. 2012;40(11):4794–4803. doi:10.1093/nar/gks06622323521
  • ZhangD, TangZ, HuangH, et al. Metabolic regulation of gene expression by histone lactylation. Nature. 2019;574(7779):575–580. doi:10.1038/s41586-019-1678-131645732
  • PatraKC, HayN. The pentose phosphate pathway and cancer. Trends Biochem Sci. 2014;39(8):347–354. doi:10.1016/j.tibs.2014.06.00525037503
  • ShackelfordDB, ShawRJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 2009;9(8):563–575. doi:10.1038/nrc267619629071
  • ParkS, SchefflerTL, RossieSS, GerrardDE. AMPK activity is regulated by calcium-mediated protein phosphatase 2A activity. Cell Calcium. 2013;53(3):217–223. doi:10.1016/j.ceca.2012.12.00123298795
  • LinR, ElfS, ShanC, et al. 6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling. Nat Cell Biol. 2015;17(11):1484–1496. doi:10.1038/ncb325526479318
  • GaoX, ZhaoL, LiuS, et al. γ-6-Phosphogluconolactone, a byproduct of the oxidative pentose phosphate pathway, contributes to AMPK activation through inhibition of PP2A. Mol Cell. 2019;76(6):857–871.e859. doi:10.1016/j.molcel.2019.09.00731586547
  • AndersonNM, MuckaP, KernJG, FengH. The emerging role and targetability of the TCA cycle in cancer metabolism. Protein Cell. 2018;9(2):216–237. doi:10.1007/s13238-017-0451-128748451
  • DangL, WhiteDW, GrossS, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739–744. doi:10.1038/nature0861719935646
  • YanH, ParsonsDW, JinG, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8):765–773. doi:10.1056/NEJMoa080871019228619
  • MardisER, DingL, DoolingDJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361(11):1058–1066. doi:10.1056/NEJMoa090384019657110
  • ParsonsDW, JonesS, ZhangX, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321(5897):1807–1812. doi:10.1126/science.116438218772396
  • YangH, YeD, GuanKL, XiongY. IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin Cancer Res. 2012;18(20):5562–5571. doi:10.1158/1078-0432.CCR-12-177323071358
  • DangL, SuSM. Isocitrate dehydrogenase mutation and (R)-2-hydroxyglutarate: from basic discovery to therapeutics development. Annu Rev Biochem. 2017;86(1):305–331. doi:10.1146/annurev-biochem-061516-04473228375741
  • FanJ, TengX, LiuL, et al. Human phosphoglycerate dehydrogenase produces the oncometabolite D-2-hydroxyglutarate. ACS Chem Biol. 2015;10(2):510–516. doi:10.1021/cb500683c25406093
  • RzemR, VincentMF, Van SchaftingenE, Veiga-da-cunhaM. L-2-hydroxyglutaric aciduria, a defect of metabolite repair. J Inherit Metab Dis. 2007;30(5):681–689. doi:10.1007/s10545-007-0487-017603759
  • IntlekoferAM, DematteoRG, VennetiS, et al. Hypoxia induces production of L-2-hydroxyglutarate. Cell Metab. 2015;22(2):304–311.26212717
  • StruysEA, SalomonsGS, AchouriY, et al. Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria. Am J Hum Genet. 2005;76(2):358–360. doi:10.1086/42789015609246
  • AchouriY, NoëlG, VertommenD, RiderMH, Veiga-da-cunhaM, Van SchaftingenE. Identification of a dehydrogenase acting on D-2-hydroxyglutarate. Biochem J. 2004;381(Pt 1):35–42. doi:10.1042/BJ2003193315070399
  • RzemR, Veiga-da-cunhaM, NoëlG, et al. A gene encoding a putative FAD-dependent L-2-hydroxyglutarate dehydrogenase is mutated in L-2-hydroxyglutaric aciduria. Proc Natl Acad Sci U S A. 2004;101(48):16849–16854. doi:10.1073/pnas.040484010115548604
  • XuW, YangH, LiuY, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19(1):17–30. doi:10.1016/j.ccr.2010.12.01421251613
  • ChowdhuryR, YeohKK, TianYM, et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 2011;12(5):463–469. doi:10.1038/embor.2011.4321460794
  • LosmanJA, KoivunenP, KaelinWGJr. 2-Oxoglutarate-dependent dioxygenases in cancer. Nat Rev Cancer. 2020;20(12):710–726.33087883
  • ShiY, WhetstineJR. Dynamic regulation of histone lysine methylation by demethylases. Mol Cell. 2007;25(1):1–14. doi:10.1016/j.molcel.2006.12.01017218267
  • LuC, WardPS, KapoorGS, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012;483(7390):474–478. doi:10.1038/nature1086022343901
  • CarbonneauM, LalondeL, LalondeM-E. The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway. Nat Commun. 2016;7(1):12700. doi:10.1038/ncomms1270027624942
  • TahilianiM, KohKP, ShenY, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324(5929):930–935. doi:10.1126/science.117011619372391
  • FigueroaME, Abdel-WahabO, LuC, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6):553–567. doi:10.1016/j.ccr.2010.11.01521130701
  • ZhaoS, LinY, XuW, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science. 2009;324(5924):261–265. doi:10.1126/science.117094419359588
  • TarhonskayaH, RydzikAM, LeungIK, et al. Non-enzymatic chemistry enables 2-hydroxyglutarate-mediated activation of 2-oxoglutarate oxygenases. Nat Commun. 2014;5(1):3423. doi:10.1038/ncomms442324594748
  • KeithB, JohnsonRS, SimonMC. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer. 2011;12(1):9–22. doi:10.1038/nrc318322169972
  • WangP, WuJ, MaS, et al. Oncometabolite D-2-hydroxyglutarate inhibits ALKBH DNA repair enzymes and sensitizes IDH mutant cells to alkylating agents. Cell Rep. 2015;13(11):2353–2361. doi:10.1016/j.celrep.2015.11.02926686626
  • GillAJ. Succinate dehydrogenase (SDH)-deficient neoplasia. Histopathology. 2018;72(1):106–116. doi:10.1111/his.1327729239034
  • ZhaoT, MuX, YouQ. Succinate: an initiator in tumorigenesis and progression. Oncotarget. 2017;8(32):53819–53828. doi:10.18632/oncotarget.1773428881853
  • RasolaA, NeckersL, PicardD. Mitochondrial oxidative phosphorylation TRAP(1)ped in tumor cells. Trends Cell Biol. 2014;24(8):455–463. doi:10.1016/j.tcb.2014.03.00524731398
  • XiaoM, YangH, XuW, et al. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 2012;26(12):1326–1338. doi:10.1101/gad.191056.11222677546
  • LetouzéE, MartinelliC, LoriotC, et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell. 2013;23(6):739–752. doi:10.1016/j.ccr.2013.04.01823707781
  • LoriotC, BurnichonN, GadessaudN, et al. Epithelial to mesenchymal transition is activated in metastatic pheochromocytomas and paragangliomas caused by SDHB gene mutations. J Clin Endocrinol Metab. 2012;97(6):E954–962. doi:10.1210/jc.2011-343722492777
  • LoriotC, DominguesM, BergerA, et al. Deciphering the molecular basis of invasiveness in Sdhb-deficient cells. Oncotarget. 2015;6(32):32955–32965. doi:10.18632/oncotarget.510626460615
  • RapizziE, ErcolinoT, FucciR, et al. Succinate dehydrogenase subunit B mutations modify human neuroblastoma cell metabolism and proliferation. Horm Cancer. 2014;5(3):174–184. doi:10.1007/s12672-014-0172-324595825
  • HoekstraAS, de GraaffMA, Briaire-de BruijnIH, et al. Inactivation of SDH and FH cause loss of 5hmC and increased H3K9me3 in paraganglioma/pheochromocytoma and smooth muscle tumors. Oncotarget. 2015;6(36):38777–38788. doi:10.18632/oncotarget.609126472283
  • SelakMA, ArmourSM, MacKenzieED, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell. 2005;7(1):77–85. doi:10.1016/j.ccr.2004.11.02215652751
  • TretterL, PatocsA, ChinopoulosC. Succinate, an intermediate in metabolism, signal transduction, ROS, hypoxia, and tumorigenesis. Biochim Biophys Acta. 2016;1857(8):1086–1101. doi:10.1016/j.bbabio.2016.03.01226971832
  • SmestadJ, ErberL, ChenY, MaherLJ3rd. Chromatin succinylation correlates with active gene expression and is perturbed by defective TCA cycle metabolism. iScience. 2018;2:63–75. doi:10.1016/j.isci.2018.03.01229888767
  • Dalla PozzaE, DandoI, PacchianaR, et al. Regulation of succinate dehydrogenase and role of succinate in cancer. Semin Cell Dev Biol. 2020;98:4–14. doi:10.1016/j.semcdb.2019.04.01331039394
  • LiuC, LiuY, ChenL, et al. Quantitative proteome and lysine succinylome analyses provide insights into metabolic regulation in breast cancer. Breast Cancer. 2019;26(1):93–105. doi:10.1007/s12282-018-0893-130022435
  • LiX, ZhangC, ZhaoT, et al. Lysine-222 succinylation reduces lysosomal degradation of lactate dehydrogenase a and is increased in gastric cancer. J Exp Clin Cancer Res. 2020;39(1):172. doi:10.1186/s13046-020-01681-032859246
  • MuX, ZhaoT, XuC, et al. Oncometabolite succinate promotes angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation. Oncotarget. 2017;8(8):13174–13185. doi:10.18632/oncotarget.1448528061458
  • WuJY, HuangTW, HsiehYT, et al. Cancer-derived succinate promotes macrophage polarization and cancer metastasis via succinate receptor. Mol Cell. 2020;77(2):213–227.e215. doi:10.1016/j.molcel.2019.10.02331735641
  • TomlinsonIP, AlamNA, RowanAJ, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002;30(4):406–410.11865300
  • BardellaC, El-BahrawyM, FrizzellN, et al. Aberrant succination of proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of mutation status. J Pathol. 2011;225(1):4–11. doi:10.1002/path.293221630274
  • BlatnikM, FrizzellN, ThorpeSR, BaynesJW. Inactivation of glyceraldehyde-3-phosphate dehydrogenase by fumarate in diabetes: formation of S-(2-succinyl)cysteine, a novel chemical modification of protein and possible biomarker of mitochondrial stress. Diabetes. 2008;57(1):41–49. doi:10.2337/db07-083817934141
  • FrizzellN, RajeshM, JepsonMJ, et al. Succination of thiol groups in adipose tissue proteins in diabetes: succination inhibits polymerization and secretion of adiponectin. J Biol Chem. 2009;284(38):25772–25781. doi:10.1074/jbc.M109.01925719592500
  • KinchL, GrishinNV, BrugarolasJ. Succination of Keap1 and activation of Nrf2-dependent antioxidant pathways in FH-deficient papillary renal cell carcinoma type 2. Cancer Cell. 2011;20(4):418–420. doi:10.1016/j.ccr.2011.10.00522014567
  • AdamJ, HatipogluE, O’FlahertyL, et al. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell. 2011;20(4):524–537. doi:10.1016/j.ccr.2011.09.00622014577
  • SullivanLB, Martinez-GarciaE, NguyenH, et al. The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling. Mol Cell. 2013;51(2):236–248. doi:10.1016/j.molcel.2013.05.00323747014
  • ZhengL, CardaciS, JerbyL, et al. Fumarate induces redox-dependent senescence by modifying glutathione metabolism. Nat Commun. 2015;6(1):6001. doi:10.1038/ncomms700125613188
  • YoshiiY, FurukawaT, SagaT, FujibayashiY. Acetate/acetyl-CoA metabolism associated with cancer fatty acid synthesis: overview and application. Cancer Lett. 2015;356(2Pt A):211–216. doi:10.1016/j.canlet.2014.02.01924569091
  • YoshiiY, WakiA, FurukawaT, et al. Tumor uptake of radiolabeled acetate reflects the expression of cytosolic acetyl-CoA synthetase: implications for the mechanism of acetate PET. Nucl Med Biol. 2009;36(7):771–777. doi:10.1016/j.nucmedbio.2009.05.00619720289
  • BauerDE, HatzivassiliouG, ZhaoF, AndreadisC, ThompsonCB. ATP citrate lyase is an important component of cell growth and transformation. Oncogene. 2005;24(41):6314–6322. doi:10.1038/sj.onc.120877316007201
  • SchugZT, PeckB, JonesDT, et al. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell. 2015;27(1):57–71. doi:10.1016/j.ccell.2014.12.00225584894
  • MetalloCM, GameiroPA, BellEL, et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature. 2011;481(7381):380–384. doi:10.1038/nature1060222101433
  • LeeJV, CarrerA, ShahS, et al. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab. 2014;20(2):306–319. doi:10.1016/j.cmet.2014.06.00424998913
  • TrefelyS, LovellCD, SnyderNW, WellenKE. Compartmentalised acyl-CoA metabolism and roles in chromatin regulation. Mol Metab. 2020;38:100941. doi:10.1016/j.molmet.2020.01.00532199817
  • McDonnellE, CrownSB, FoxDB, et al. Lipids reprogram metabolism to become a major carbon source for histone acetylation. Cell Rep. 2016;17(6):1463–1472. doi:10.1016/j.celrep.2016.10.01227806287
  • CarrerA, TrefelyS, ZhaoS, et al. Acetyl-CoA metabolism supports multistep pancreatic tumorigenesis. Cancer Discov. 2019;9(3):416–435. doi:10.1158/2159-8290.CD-18-056730626590
  • ZhengZQ, LiZX, GuanJL, et al. Long noncoding RNA TINCR-mediated regulation of acetyl-CoA metabolism promotes nasopharyngeal carcinoma progression and chemoresistance. Cancer Res. 2020;80(23):5174–5188. doi:10.1158/0008-5472.CAN-19-362633067266
  • GaoX, LinSH, RenF, et al. Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia. Nat Commun. 2016;7(1):11960. doi:10.1038/ncomms1196027357947
  • LinR, TaoR, GaoX, et al. Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth. Mol Cell. 2013;51(4):506–518. doi:10.1016/j.molcel.2013.07.00223932781
  • ChenD, XiaS, ZhangR, et al. Lysine acetylation restricts mutant IDH2 activity to optimize transformation in AML cells. Mol Cell. 2021;S1097-2765(21)00507-4. doi:10.1016/j.molcel.2021.06.027
  • BoseS, RameshV, LocasaleJW. Acetate metabolism in physiology, cancer, and beyond. Trends Cell Biol. 2019;29(9):695–703. doi:10.1016/j.tcb.2019.05.00531160120
  • SchugZT, Vande VoordeJ, GottliebE. The metabolic fate of acetate in cancer. Nat Rev Cancer. 2016;16(11):708–717. doi:10.1038/nrc.2016.8727562461
  • HatanakaH, TsukuiM, TakadaS, et al. Identification of transforming activity of free fatty acid receptor 2 by retroviral expression screening. Cancer Sci. 2010;101(1):54–59. doi:10.1111/j.1349-7006.2009.01348.x19780758
  • YonezawaT, KobayashiY, ObaraY. Short-chain fatty acids induce acute phosphorylation of the p38 mitogen-activated protein kinase/heat shock protein 27 pathway via GPR43 in the MCF-7 human breast cancer cell line. Cell Signal. 2007;19(1):185–193. doi:10.1016/j.cellsig.2006.06.00416887331
  • LeviL, WangZ, DoudMK, HazenSL, NoyN. Saturated fatty acids regulate retinoic acid signalling and suppress tumorigenesis by targeting fatty acid-binding protein 5. Nat Commun. 2015;6(1):8794. doi:10.1038/ncomms979426592976
  • ArmstrongEH, GoswamiD, GriffinPR, NoyN, OrtlundEA. Structural basis for ligand regulation of the fatty acid-binding protein 5, peroxisome proliferator-activated receptor β/δ (FABP5-PPARβ/δ) signaling pathway. J Biol Chem. 2014;289(21):14941–14954. doi:10.1074/jbc.M113.51464624692551
  • LongoR, PeriC, CricrìD, et al. Ketogenic diet: a new light shining on old but gold biochemistry. Nutrients. 2019;11(10):2497. doi:10.3390/nu11102497
  • AbdelmegeedMA, KimSK, WoodcroftKJ, NovakRF. Acetoacetate activation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase in primary cultured rat hepatocytes: role of oxidative stress. J Pharmacol Exp Ther. 2004;310(2):728–736. doi:10.1124/jpet.104.06652215051799
  • KangHB, FanJ, LinR, et al. Metabolic rewiring by oncogenic BRAF V600E links ketogenesis pathway to BRAF-MEK1 signaling. Mol Cell. 2015;59(3):345–358. doi:10.1016/j.molcel.2015.05.03726145173
  • ZhaoL, FanJ, XiaS, et al. HMG-CoA synthase 1 is a synthetic lethal partner of BRAF(V600E) in human cancers. J Biol Chem. 2017;292(24):10142–10152. doi:10.1074/jbc.M117.78877828468827
  • XiaS, LinR, JinL, et al. Prevention of dietary-fat-fueled ketogenesis attenuates BRAF V600E tumor growth. Cell Metab. 2017;25(2):358–373. doi:10.1016/j.cmet.2016.12.01028089569
  • NewmanJC, VerdinE. β-hydroxybutyrate: much more than a metabolite. Diabetes Res Clin Pract. 2014;106(2):173–181. doi:10.1016/j.diabres.2014.08.00925193333
  • NewmanJC, VerdinE. Ketone bodies as signaling metabolites. Trends Endocrinol Metab. 2014;25(1):42–52. doi:10.1016/j.tem.2013.09.00224140022
  • MollerN. Ketone body, 3-hydroxybutyrate: minor metabolite - major medical manifestations. J Clin Endocrinol Metab. 2020;105(9):2884–2892. doi:10.1210/clinem/dgaa370
  • DabekA, WojtalaM, PirolaL, BalcerczykA. Modulation of cellular biochemistry, epigenetics and metabolomics by ketone bodies. Implications of the ketogenic diet in the physiology of the organism and pathological states. Nutrients. 2020;12(3):788. doi:10.3390/nu12030788
  • ShimazuT, HirscheyMD, NewmanJ, et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science. 2013;339(6116):211–214. doi:10.1126/science.122716623223453
  • XieZ, ZhangD, ChungD, et al. Metabolic regulation of gene expression by histone lysine β-hydroxybutyrylation. Mol Cell. 2016;62(2):194–206. doi:10.1016/j.molcel.2016.03.03627105115
  • LiuK, LiF, SunQ, et al. p53 β-hydroxybutyrylation attenuates p53 activity. Cell Death Dis. 2019;10(3):243. doi:10.1038/s41419-019-1463-y30858356
  • RisticB, BhutiaYD, GanapathyV. Cell-surface G-protein-coupled receptors for tumor-associated metabolites: a direct link to mitochondrial dysfunction in cancer. Biochim Biophys Acta Rev Cancer. 2017;1868(1):246–257. doi:10.1016/j.bbcan.2017.05.00328512002
  • SandersonSM, GaoX, DaiZ, LocasaleJW. Methionine metabolism in health and cancer: a nexus of diet and precision medicine. Nat Rev Cancer. 2019;19(11):625–637. doi:10.1038/s41568-019-0187-831515518
  • SchmidtT, LehaA, Salinas-RiesterG. Treatment of prostate cancer cells with S-adenosylmethionine leads to genome-wide alterations in transcription profiles. Gene. 2016;595(2):161–167. doi:10.1016/j.gene.2016.09.03227688072
  • MentchSJ, MehrmohamadiM, HuangL, et al. Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism. Cell Metab. 2015;22(5):861–873. doi:10.1016/j.cmet.2015.08.02426411344
  • ShukeirN, PakneshanP, ChenG, SzyfM, RabbaniSA. Alteration of the methylation status of tumor-promoting genes decreases prostate cancer cell invasiveness and tumorigenesis in vitro and in vivo. Cancer Res. 2006;66(18):9202–9210. doi:10.1158/0008-5472.CAN-06-195416982764
  • ChikF, MachnesZ, SzyfM. Synergistic anti-breast cancer effect of a combined treatment with the methyl donor S-adenosyl methionine and the DNA methylation inhibitor 5-aza-2ʹ-deoxycytidine. Carcinogenesis. 2014;35(1):138–144. doi:10.1093/carcin/bgt28423985780
  • LuoJ, LiYN, WangF, ZhangWM, GengX. S-adenosylmethionine inhibits the growth of cancer cells by reversing the hypomethylation status of c-myc and H-ras in human gastric cancer and colon cancer. Int J Biol Sci. 2010;6(7):784–795. doi:10.7150/ijbs.6.78421152119
  • LiTW, YangH, PengH, XiaM, MatoJM, LuSC. Effects of S-adenosylmethionine and methylthioadenosine on inflammation-induced colon cancer in mice. Carcinogenesis. 2012;33(2):427–435. doi:10.1093/carcin/bgr29522159228
  • LiTW, PengH, YangH, et al. S-Adenosylmethionine and methylthioadenosine inhibit β-catenin signaling by multiple mechanisms in liver and colon cancer. Mol Pharmacol. 2015;87(1):77–86. doi:10.1124/mol.114.09567925338671
  • IlissoCP, SapioL, Delle CaveD, et al. S-Adenosylmethionine affects ERK1/2 and Stat3 pathways and induces apotosis in osteosarcoma cells. J Cell Physiol. 2016;231(2):428–435. doi:10.1002/jcp.2508926174106
  • AltmanBJ, StineZE, DangCV. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer. 2016;16(10):619–634. doi:10.1038/nrc.2016.7127492215
  • BansalA, SimonMC. Glutathione metabolism in cancer progression and treatment resistance. J Cell Biol. 2018;217(7):2291–2298. doi:10.1083/jcb.20180416129915025
  • SinghS, KhanAR, GuptaAK. Role of glutathione in cancer pathophysiology and therapeutic interventions. J Exp Ther Oncol. 2012;9(4):303–316.22545423
  • ZhangJ, YeZW, SinghS, TownsendDM, TewKD. An evolving understanding of the S-glutathionylation cycle in pathways of redox regulation. Free Radic Biol Med. 2018;120:204–216. doi:10.1016/j.freeradbiomed.2018.03.03829578070
  • TewKD, ManevichY, GrekC, XiongY, UysJ, TownsendDM. The role of glutathione S-transferase P in signaling pathways and S-glutathionylation in cancer. Free Radic Biol Med. 2011;51(2):299–313. doi:10.1016/j.freeradbiomed.2011.04.01321558000
  • García-GiménezJL, ÒlasoG, HakeSB, et al. Histone h3 glutathionylation in proliferating mammalian cells destabilizes nucleosomal structure. Antioxid Redox Signal. 2013;19(12):1305–1320. doi:10.1089/ars.2012.502123541030
  • PlattenM, NollenEAA, RohrigUF, FallarinoF, OpitzCA. Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat Rev Drug Discov. 2019;18(5):379–401.30760888
  • LiuXH, ZhaiXY. Role of tryptophan metabolism in cancers and therapeutic implications. Biochimie. 2021;182:131–139. doi:10.1016/j.biochi.2021.01.00533460767
  • WalczakK, LangnerE, Makuch-KockaA, et al. Effect of tryptophan-derived ahr ligands, kynurenine, kynurenic acid and FICZ, on proliferation, cell cycle regulation and cell death of melanoma cells-in vitro studies. Int J Mol Sci. 2020;21(21):7946. doi:10.3390/ijms21217946
  • KolluriSK, JinUH, SafeS. Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target. Arch Toxicol. 2017;91(7):2497–2513. doi:10.1007/s00204-017-1981-228508231
  • VenkateswaranN, Lafita-NavarroMC, HaoYH, et al. MYC promotes tryptophan uptake and metabolism by the kynurenine pathway in colon cancer. Genes Dev. 2019;33(17–18):1236–1251. doi:10.1101/gad.327056.11931416966
  • CampesatoLF, BudhuS, TchaichaJ, et al. Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine. Nat Commun. 2020;11(1):4011. doi:10.1038/s41467-020-17750-z32782249
  • DiNataleBC, MurrayIA, SchroederJC, et al. Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling. Toxicol Sci. 2010;115(1):89–97. doi:10.1093/toxsci/kfq02420106948
  • WalczakK, WnorowskiA, TurskiWA, PlechT. Kynurenic acid and cancer: facts and controversies. Cell Mol Life Sci. 2020;77(8):1531–1550. doi:10.1007/s00018-019-03332-w31659416
  • WalczakK, Deneka-HannemannS, JaroszB, et al. Kynurenic acid inhibits proliferation and migration of human glioblastoma T98G cells. Pharmacol Rep. 2014;66(1):130–136. doi:10.1016/j.pharep.2013.06.00724905318