Therapeutic Targeting of Mitochondrial One-Carbon Metabolism in Cancer

Hanahan, 2011, Hallmarks of cancer: the next generation, Cell, 144, 646, 10.1016/j.cell.2011.02.013

Visentin, 2012, The antifolates, Hematol Oncol Clin North Am, 26, 629, 10.1016/j.hoc.2012.02.002

Grem, 2000, 5-fluorouracil: forty-plus and still ticking. A review of its preclinical and clinical development, Invest New Drugs, 18, 299, 10.1023/A:1006416410198

Ducker, 2017, One-carbon metabolism in health and disease, Cell Metab, 25, 27, 10.1016/j.cmet.2016.08.009

Locasale, 2013, Serine, glycine and the one-carbon cycle: cancer metabolism in full circle, Nat Rev Cancer, 13, 572, 10.1038/nrc3557

Ye, 2014, Serine catabolism regulates mitochondrial redox control during hypoxia, Cancer Discov, 4, 1406, 10.1158/2159-8290.CD-14-0250

Yang, 2016, Serine and one-carbon metabolism in cancer, Nat Rev Cancer, 16, 650, 10.1038/nrc.2016.81

Newman, 2017, One-carbon metabolism in cancer, Br J Cancer, 116, 1499, 10.1038/bjc.2017.118

Liu, 2019, High expression of SHMT2 is correlated with tumor progression and predicts poor prognosis in gastrointestinal tumors, Eur Rev Med Pharmacol Sci, 23, 9379

Ning, 2018, SHMT2 overexpression predicts poor prognosis in intrahepatic cholangiocarcinoma, Gastroenterol Res Pract, 2018, 4369253, 10.1155/2018/4369253

Noguchi, 2018, The mitochondrial one-carbon metabolic pathway is associated with patient survival in pancreatic cancer, Oncol Lett, 16, 1827

Yin, 2015, Positive correlation between expression level of mitochondrial serine hydroxymethyltransferase and breast cancer grade, Onco Targets Ther, 8, 1069, 10.2147/OTT.S82433

Liu, 2014, Increased MTHFD2 expression is associated with poor prognosis in breast cancer, Tumour Biol, 35, 8685, 10.1007/s13277-014-2111-x

Kim, 2015, SHMT2 drives glioma cell survival in the tumor microenvironment but imposes a dependence on glycine clearance, Nature, 520, 363, 10.1038/nature14363

Stokstad, 1990, Historical perspective on key advances in the biochemistry and physiology of folates

Appling, 1991, Compartmentation of folate-mediated one-carbon metabolism in eukaryotes, FASEB J, 5, 2645, 10.1096/fasebj.5.12.1916088

Matherly, 2007, Human reduced folate carrier: translation of basic biology to cancer etiology and therapy, Cancer Metastasis Rev, 26, 111, 10.1007/s10555-007-9046-2

Matherly, 2014, The major facilitative folate transporters solute carrier 19A1 and solute carrier 46A1: biology and role in antifolate chemotherapy of cancer, Drug Metab Dispos, 42, 632, 10.1124/dmd.113.055723

Zhao, 2011, Mechanisms of membrane transport of folates into cells and across epithelia, Annu Rev Nutr, 31, 177, 10.1146/annurev-nutr-072610-145133

Desmoulin, 2012, The human proton-coupled folate transporter: biology and therapeutic applications to cancer, Cancer Biol Ther, 13, 1355, 10.4161/cbt.22020

Qiu, 2007, Rodent intestinal folate transporters (SLC46A1): secondary structure, functional properties, and response to dietary folate restriction, Am J Physiol Cell Physiol, 293, C1669, 10.1152/ajpcell.00202.2007

Zhao, 2013, Inhibition of the proton-coupled folate transporter (PCFT-SLC46A1) by bicarbonate and other anions, Mol Pharmacol, 84, 95, 10.1124/mol.113.085605

Matherly, 2018, The promise and challenges of exploiting the proton-coupled folate transporter for selective therapeutic targeting of cancer, Cancer Chemother Pharmacol, 81, 1, 10.1007/s00280-017-3473-8

Wilson, 2016, Targeting nonsquamous nonsmall cell lung cancer via the proton-coupled folate transporter with 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates, Mol Pharmacol, 89, 425, 10.1124/mol.115.102798

Giovannetti, 2017, Role of proton-coupled folate transporter in pemetrexed resistance of mesothelioma: clinical evidence and new pharmacological tools, Ann Oncol, 28, 2725, 10.1093/annonc/mdx499

Hou, 2017, Dual targeting of epithelial ovarian cancer via folate receptor alpha and the proton-coupled folate transporter with 6-substituted pyrrolo[2,3-d]pyrimidine antifolates, Mol Cancer Ther, 16, 819, 10.1158/1535-7163.MCT-16-0444

Dekhne, 2020, Cellular pharmacodynamics of a novel pyrrolo[3,2-d]pyrimidine inhibitor targeting mitochondrial and cytosolic one-carbon metabolism, Mol Pharmacol, 97, 9, 10.1124/mol.119.117937

Tibbetts, 2010, Compartmentalization of Mammalian folate-mediated one-carbon metabolism, Ann Rev Nutr, 30, 57, 10.1146/annurev.nutr.012809.104810

Field, 2018, Nuclear folate metabolism, Ann Rev Nutr, 38, 219, 10.1146/annurev-nutr-071714-034441

Lawrence, 2011, Tetrahydrofolate recognition by the mitochondrial folate transporter, J Biol Chem, 286, 31480, 10.1074/jbc.M111.272187

McCarthy, 2004, A mutation inactivating the mitochondrial inner membrane folate transporter creates a glycine requirement for survival of Chinese hamster cells, J Biol Chem, 279, 33829, 10.1074/jbc.M403677200

Kuan, 1993, The mitochondrial carrier family of transport proteins: structural, functional, and evolutionary relationships, Crit Rev Biochem Mol Biol, 28, 209, 10.3109/10409239309086795

Lawrence, 2014, Mammalian mitochondrial and cytosolic folylpolyglutamate synthetase maintain the subcellular compartmentalization of folates, J Biol Chem, 289, 29386, 10.1074/jbc.M114.593244

Shane, 1989, Folylpolyglutamate synthesis and role in the regulation of one-carbon metabolism, Vitam Horm, 45, 263, 10.1016/S0083-6729(08)60397-0

Dekhne, 2019, Novel pyrrolo[3,2-d]pyrimidine compounds target mitochondrial and cytosolic one-carbon metabolism with broad-spectrum antitumor efficacy, Mol Cancer Ther, 10, 1787, 10.1158/1535-7163.MCT-19-0037

Ducker, 2017, Human SHMT inhibitors reveal defective glycine import as a targetable metabolic vulnerability of diffuse large B-cell lymphoma, Proc Natl Acad Sci U S A, 114, 11404, 10.1073/pnas.1706617114

Tang, 2020, Blockade of glutathione metabolism in IDH1-mutated glioma, Mol Cancer Ther, 19, 221, 10.1158/1535-7163.MCT-19-0103

Hum, 1988, Primary structure of a human trifunctional enzyme. Isolation of a cDNA encoding methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase, J Biol Chem, 263, 15946, 10.1016/S0021-9258(18)37540-9

Pedley, 2017, A new view into the regulation of purine metabolism: the purinosome, Trends Biochem Sci, 42, 141, 10.1016/j.tibs.2016.09.009

Anderson, 2011, Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria, Proc Natl Acad Sci U S A, 108, 15163, 10.1073/pnas.1103623108

Wong, 2001, Nuclear thymidylate synthase expression, p53 expression and 5FU response in colorectal carcinoma, Br J Cancer, 85, 1937, 10.1054/bjoc.2001.2175

Matthews, 1986, Methylenetetrahydrofolate reductase from pig liver, Methods Enzymol, 122, 372, 10.1016/0076-6879(86)22196-5

Chen, 1997, Human methionine synthase. cDNA cloning, gene localization, and expression, J Biol Chem, 272, 3628, 10.1074/jbc.272.6.3628

Lu, 2000, S-adenosylmethionine, Int J Biochem Cell Biol, 32, 391, 10.1016/S1357-2725(99)00139-9

Ducker, 2016, Reversal of cytosolic one-carbon flux compensates for loss of the mitochondrial folate pathway, Cell Metab, 23, 1140, 10.1016/j.cmet.2016.04.016

Guiducci, 2019, The moonlighting RNA-binding activity of cytosolic serine hydroxymethyltransferase contributes to control compartmentalization of serine metabolism, Nucleic Acids Res, 47, 4240, 10.1093/nar/gkz129

Anderson, 2009, SHMT1 and SHMT2 are functionally redundant in nuclear de novo thymidylate biosynthesis, PLoS One, 4, e5839, 10.1371/journal.pone.0005839

Meiser, 2016, Give it or take it: the flux of one-carbon in cancer cells, FEBS J, 283, 3695, 10.1111/febs.13731

Murthy, 2006, Replitase: complete machinery for DNA synthesis, J Cell Phys, 209, 711, 10.1002/jcp.20842

Gustafsson Sheppard, 2015, The folate-coupled enzyme MTHFD2 is a nuclear protein and promotes cell proliferation, Sci Rep, 5, 15029, 10.1038/srep15029

Koufaris, 2018, Protein interaction and functional data indicate MTHFD2 involvement in RNA processing and translation, Cancer Metab, 6, 12, 10.1186/s40170-018-0185-4

Green, 2019, MTHFD2 links RNA methylation to metabolic reprogramming in renal cell carcinoma, Oncogene, 38, 6211, 10.1038/s41388-019-0869-4

Possemato, 2011, Functional genomics reveal that the serine synthesis pathway is essential in breast cancer, Nature, 476, 346, 10.1038/nature10350

Amelio, 2014, Serine and glycine metabolism in cancer, Trends Biochem Sci, 39, 191, 10.1016/j.tibs.2014.02.004

Locasale, 2011, Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis, Nat Genet, 43, 869, 10.1038/ng.890

Sugimoto, 1968, The mechanism of end product inhibition of serine biosynthesis. I. Purification and kinetics of phosphoglycerate dehydrogenase, J Biol Chem, 243, 2081, 10.1016/S0021-9258(18)93450-2

Chaneton, 2012, Serine is a natural ligand and allosteric activator of pyruvate kinase M2, Nature, 491, 458, 10.1038/nature11540

Kory, 2018, SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism, Science, 362, eaat9528, 10.1126/science.aat9528

Nilsson, 2014, Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer, Nat Commun, 5, 4128, 10.1038/ncomms4128

Jain, 2012, Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation, Science, 336, 1040, 10.1126/science.1218595

Badar, 2015, Detectable FLT3-ITD or RAS mutation at the time of transformation from MDS to AML predicts for very poor outcomes, Leuk Res, 39, 1367, 10.1016/j.leukres.2015.10.005

Nikiforov, 2002, A functional screen for Myc-responsive genes reveals serine hydroxymethyltransferase, a major source of the one-carbon unit for cell metabolism, Mol Cell Biol, 22, 5793, 10.1128/MCB.22.16.5793-5800.2002

Shin, 2017, Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase, Cancer Metab, 5, 11, 10.1186/s40170-017-0173-0

Li, 2020, Metabolic profiling reveals a dependency of human metastatic breast cancer on mitochondrial serine and one-carbon unit metabolism, Mol Cancer Res, 18, 599, 10.1158/1541-7786.MCR-19-0606

Zhang, 2016, Prognostic and therapeutic value of mitochondrial serine hydroxyl-methyltransferase 2 as a breast cancer biomarker, Oncol Rep, 36, 2489, 10.3892/or.2016.5112

DeNicola, 2015, NRF2 regulates serine biosynthesis in non-small cell lung cancer, Nat Genet, 47, 1475, 10.1038/ng.3421

Wu, 2017, Overexpression of mitochondrial serine hydroxyl-methyltransferase 2 is associated with poor prognosis and promotes cell proliferation and invasion in gliomas, Onco Targets Ther, 10, 3781, 10.2147/OTT.S130409

Fan, 2014, Quantitative flux analysis reveals folate-dependent NADPH production, Nature, 510, 298, 10.1038/nature13236

di Salvo, 2013, Glycine consumption and mitochondrial serine hydroxymethyltransferase in cancer cells: the heme connection, Med Hypotheses, 80, 633, 10.1016/j.mehy.2013.02.008

Morscher, 2018, Mitochondrial translation requires folate-dependent tRNA methylation, Nature, 554, 128, 10.1038/nature25460

Minton, 2018, Serine catabolism by SHMT2 is required for proper mitochondrial translation initiation and maintenance of formylmethionyl-tRNAs, Mol Cell, 69, 610, 10.1016/j.molcel.2018.01.024

Witt, 2009, HDAC family: what are the cancer relevant targets?, Cancer Lett, 277, 8, 10.1016/j.canlet.2008.08.016

Yang, 2018, SHMT2 desuccinylation by SIRT5 drives cancer cell proliferation, Cancer Res, 78, 372, 10.1158/0008-5472.CAN-17-1912

Giardina, 2015, How pyridoxal 5′-phosphate differentially regulates human cytosolic and mitochondrial serine hydroxymethyltransferase oligomeric state, FEBS J, 282, 1225, 10.1111/febs.13211

Walden, 2019, Metabolic control of BRISC-SHMT2 assembly regulates immune signalling, Nature, 570, 194, 10.1038/s41586-019-1232-1

Cao, 2019, HDAC11 regulates type I interferon signaling through defatty-acylation of SHMT2, Proc Natl Acad Sci U S A, 116, 5487, 10.1073/pnas.1815365116

Deubzer, 2013, HDAC11 is a novel drug target in carcinomas, Int J Cancer, 132, 2200, 10.1002/ijc.27876

Christensen, 2008, Mitochondrial methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase, and formyltetrahydrofolate synthetases, Vitam Horm, 79, 393, 10.1016/S0083-6729(08)00414-7

Shin, 2014, Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues, J Biol Chem, 289, 15507, 10.1074/jbc.M114.555573

Nilsson, 2019, Mitochondrial MTHFD isozymes display distinct expression, regulation, and association with cancer, Gene, 716, 144032, 10.1016/j.gene.2019.144032

Pikman, 2016, Targeting MTHFD2 in acute myeloid leukemia, J Exp Med, 213, 1285, 10.1084/jem.20151574

Ben-Sahra, 2016, mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle, Science, 351, 728, 10.1126/science.aad0489

Nishimura, 2019, Cancer stem-like properties and gefitinib resistance are dependent on purine synthetic metabolism mediated by the mitochondrial enzyme MTHFD2, Oncogene, 38, 2464, 10.1038/s41388-018-0589-1

Meiser, 2016, Serine one-carbon catabolism with formate overflow, Sci Adv, 2, e1601273, 10.1126/sciadv.1601273

Meiser, 2018, Increased formate overflow is a hallmark of oxidative cancer, Nat Commun, 9, 368, 10.1038/s41467-018-03777-w

Zheng, 2018, Mitochondrial one-carbon pathway supports cytosolic folate integrity in cancer cells, Cell, 175, 1546, 10.1016/j.cell.2018.09.041

Kikuchi, 2008, Glycine cleavage system: reaction mechanism, physiological significance, and hyperglycinemia, Proc Jpn Acad Ser B Phys Biol Sci, 84, 246, 10.2183/pjab.84.246

Zhang, 2012, Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis, Cell, 148, 259, 10.1016/j.cell.2011.11.050

Labuschagne, 2014, Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells, Cell Rep, 7, 1248, 10.1016/j.celrep.2014.04.045

Krupenko, 2018, ALDH1L1 and ALDH1L2 folate regulatory enzymes in cancer, Adv Exp Med Biol, 1032, 127, 10.1007/978-3-319-98788-0_10

Piskounova, 2015, Oxidative stress inhibits distant metastasis by human melanoma cells, Nature, 527, 186, 10.1038/nature15726

Wu, 2019, Nrf2 in cancers: a double-edged sword, Cancer Med, 8, 2252, 10.1002/cam4.2101

Okazaki, 2020, Metabolic features of cancer cells in NRF2 addiction status, Biophys Rev, 12, 435, 10.1007/s12551-020-00659-8

Yu, 2020, Triptolide suppresses IDH1-mutated malignancy via Nrf2-driven glutathione metabolism, Proc Natl Acad Sci U S A, 117, 9964, 10.1073/pnas.1913633117

Mitsuishi, 2012, Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming, Cancer Cell, 22, 66, 10.1016/j.ccr.2012.05.016

Maddocks, 2013, Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells, Nature, 493, 542, 10.1038/nature11743

Lehtinen, 2013, High-throughput RNAi screening for novel modulators of vimentin expression identifies MTHFD2 as a regulator of breast cancer cell migration and invasion, Oncotarget, 4, 48, 10.18632/oncotarget.756

Koufaris, 2016, Suppression of MTHFD2 in MCF-7 breast cancer cells increases glycolysis, dependency on exogenous glycine, and sensitivity to folate depletion, J Proteome Res, 15, 2618, 10.1021/acs.jproteome.6b00188

Schmidt, 2000, Structures of three inhibitor complexes provide insight into the reaction mechanism of the human methylenetetrahydrofolate dehydrogenase/cyclohydrolase, Biochem J, 39, 6325, 10.1021/bi992734y

Eadsforth, 2012, Assessment of Pseudomonas aeruginosa N5,N10-methylenetetrahydrofolate dehydrogenase-cyclohydrolase as a potential antibacterial drug target, PLoS One, 7, e35973, 10.1371/journal.pone.0035973

Fu, 2017, The natural product carolacton inhibits folate-dependent C1 metabolism by targeting FolD/MTHFD, Nat Commun, 8, 1529, 10.1038/s41467-017-01671-5

Gustafsson, 2017, Crystal structure of the emerging cancer target MTHFD2 in complex with a substrate-based inhibitor, Cancer Res, 77, 937, 10.1158/0008-5472.CAN-16-1476

Ju, 2019, Modulation of redox homeostasis by inhibition of MTHFD2 in colorectal cancer: mechanisms and therapeutic implications, J Natl Cancer Inst, 111, 584, 10.1093/jnci/djy160

Kawai, 2019, Structure-based design and synthesis of an isozyme-selective MTHFD2 inhibitor with a tricyclic coumarin scaffold, ACS Med Chem Lett, 10, 893, 10.1021/acsmedchemlett.9b00069

Kawai, 2019, Discovery of a potent, selective, and orally available MTHFD2 inhibitor (DS18561882) with in vivo antitumor activity, J Med Chem, 62, 10204, 10.1021/acs.jmedchem.9b01113

Paiardini, 2015, Screening and in vitro testing of antifolate inhibitors of human cytosolic serine hydroxymethyltransferase, ChemMedChem, 10, 490, 10.1002/cmdc.201500028

Daidone, 2011, In silico and in vitro validation of serine hydroxymethyltransferase as a chemotherapeutic target of the antifolate drug pemetrexed, Eur J Med Chem, 46, 1616, 10.1016/j.ejmech.2011.02.009

Shih, 1997, LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes, Cancer Res, 57, 1116

Scaletti, 2019, Structural basis of inhibition of the human serine hydroxymethyltransferase SHMT2 by antifolate drugs, FEBS Lett, 593, 1863, 10.1002/1873-3468.13455

Witschel, 2013, Pyrazolopyrans having herbicidal and pharmaceutical properties

Witschel, 2015, Inhibitors of plasmodial serine hydroxymethyltransferase (SHMT): cocrystal structures of pyrazolopyrans with potent blood- and liver-stage activities, J Med Chem, 58, 3117, 10.1021/jm501987h

Marani, 2016, A pyrazolopyran derivative preferentially inhibits the activity of human cytosolic serine hydroxymethyltransferase and induces cell death in lung cancer cells, Oncotarget, 7, 4570, 10.18632/oncotarget.6726

Ma, 2017, Serine is an essential metabolite for effector T cell expansion, Cell Metab, 25, 345, 10.1016/j.cmet.2016.12.011

García-Cañaveras, 2020, SHMT inhibition is effective and synergizes with methotrexate in T-cell acute lymphoblastic leukemia, Leukemia

Mitchell-Ryan, 2013, Discovery of 5-substituted pyrrolo[2,3-d]pyrimidine antifolates as dual acting inhibitors of glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase in de novo purine nucleotide biosynthesis: implications of inhibiting 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase to AMPK activation and anti-tumor activity, J Med Chem, 56, 10016, 10.1021/jm401328u

Chang, 2007, Serine hydroxymethyltransferase isoforms are differentially inhibited by leucovorin: characterization and comparison of recombinant zebrafish serine hydroxymethyltransferases, Drug Metab Dispos, 35, 2127, 10.1124/dmd.107.016840

Anderson, 2012, Serine hydroxymethyltransferase anchors de novo thymidylate synthesis pathway to nuclear lamina for DNA synthesis, J Biol Chem, 287, 7051, 10.1074/jbc.M111.333120

Bronder, 2002, Antifolates targeting purine synthesis allow entry of tumor cells into S phase regardless of p53 function, Cancer Res, 62, 5236

Hoxhaj, 2017, The mTORC1 signaling network senses changes in cellular purine nucleotide levels, Cell Rep, 21, 1331, 10.1016/j.celrep.2017.10.029

Bertino, 2011, Targeting tumors that lack methylthioadenosine phosphorylase (MTAP) activity: current strategies, Cancer Biol Ther, 11, 627, 10.4161/cbt.11.7.14948

Goveia, 2016, Meta-analysis of clinical metabolic profiling studies in cancer: challenges and opportunities, EMBO Mol Med, 8, 1134, 10.15252/emmm.201606798

Ravez, 2017, Challenges and opportunities in the development of serine synthetic pathway inhibitors for cancer therapy, J Med Chem, 60, 1227, 10.1021/acs.jmedchem.6b01167

Linares, 2017, ATF4-Induced metabolic reprograming is a synthetic vulnerability of the p62-deficient tumor stroma, Cell Metab, 26, 817, 10.1016/j.cmet.2017.09.001

Cochran, 2019, Bromodomains: a new target class for drug development, Nat Rev Drug Discov, 18, 609, 10.1038/s41573-019-0030-7