Reversal of cytosolic one-carbon flux compensates for loss of the mitochondrial folate pathway
Open accessAbstract
One-carbon (1C) units for purine and thymidine synthesis can be generated from serine by cytosolic or mitochondrial folate metabolism. The mitochondrial 1C pathway is consistently overexpressed in cancer. Here, we show that most but not all proliferating mammalian cell lines use the mitochondrial pathway as the default for making 1C units. Clustered regularly interspaced short palindromic repeats (CRISPR)-mediated mitochondrial pathway knockout activates cytosolic 1C-unit production. This reversal in cytosolic flux is triggered by depletion of a single metabolite, 10-formyl-tetrahydrofolate (10-formyl-THF), and enables rapid cell growth in nutrient-replete conditions. Loss of the mitochondrial pathway, however, renders cells dependent on extracellular serine to make 1C units and on extracellular glycine to make glutathione. HCT-116 colon cancer xenografts lacking mitochondrial 1C pathway activity generate the 1C units required for growth by cytosolic serine catabolism. Loss of both pathways precludes xenograft formation. Thus, either mitochondrial or cytosolic 1C metabolism can support tumorigenesis, with the mitochondrial pathway required in nutrient-poor conditions.
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Eliminating environmental serine, limiting aspartate synthesis via mitochondrial inhibition, and ablating the mitochondrial folate pathway impair purine biosynthesis.
“For example, eliminating environmental serine, limiting aspartate synthesis via mitochondrial inhibition, and ablating the mitochondrial folate pathway impairs purine biosynthesis (Ducker et al., 2016; Labuschagne et al., 2014; Sullivan et al., 2015).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Ducker et al., 2016
In the absence of SHMT2, cytosolic SHMT1 reverses flux to compensate.
“In the absence of SHMT2, cytosolic SHMT1 reverses flux to compensate69”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [69]
When the mitochondrial folate pathway is inhibited, the cytosolic pathway reverses flux to compensate; therefore, inhibition of both SHMT isoforms is essential for antitumor activity.
“Additionally, when the mitochondrial folate pathway is inhibited, the cytosolic pathway reverses flux to compensate; therefore, inhibition of both isoforms is essential for antitumor activity.”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [158]
MTHFD2 plays a role in redox homeostasis through its cofactor NAD+ and through involvement with expression of hypoxia-related proteins such as HIF-2α.
“In addition to its involvement in nutrient regulation, MTHFD2 plays a role in redox homeostasis through the use of its cofactor NAD+, as well as involvement with expression of hypoxia-related proteins such as HIF-2α.”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [158]
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Cites
Genome engineering using the CRISPR-Cas9 system
Ran, F. A., Hsu, P. D., Wright, J., Agarwala, V., Scott, D. A., & Zhang, F. (2013) · Nature Protocols · doi:10.1038/nprot.2013.143 · Cited by 11,133 · see citing works
Analysis of protein-coding genetic variation in 60,706 humans
Exome Aggregation Consortium, Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O’Donnell-Luria, A. H., Ware, J. S., Hill, A. J., et al. (2016) · Nature · doi:10.1038/nature19057 · Cited by 9,587 · see citing works
5-Fluorouracil: mechanisms of action and clinical strategies
Longley, D. B., Harkin, D. P., & Johnston, P. G. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1074 · Cited by 5,332 · see citing works
Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity
Ran, F. A., Hsu, P. D., Lin, C.-Y., Gootenberg, J. S., Konermann, S., Trevino, A. E., Scott, D. A., Inoue, A., Matoba, S., Zhang, Y., et al. (2013) · Cell · doi:10.1016/j.cell.2013.08.021 · Cited by 3,299 · see citing works
Cellular energy utilization and molecular origin of standard metabolic rate in mammals
Rolfe, D. F., & Brown, G. C. (1997) · Physiological Reviews · doi:10.1152/physrev.1997.77.3.731 · Cited by 2,021 · see citing works
Functional genomics reveal that the serine synthesis pathway is essential in breast cancer
Possemato, R., Marks, K. M., Shaul, Y. D., Pacold, M. E., Kim, D., Birsoy, K., Sethumadhavan, S., Woo, H.-K., Jang, H. G., Jha, A. K., et al. (2011) · Nature · doi:10.1038/nature10350 · Cited by 1,683 · see citing works
Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation
Jain, M., Nilsson, R., Sharma, S., Madhusudhan, N., Kitami, T., Souza, A. L., Kafri, R., Kirschner, M. W., Clish, C. B., & Mootha, V. K. (2012) · Science · doi:10.1126/science.1218595 · Cited by 1,403 · see citing works
Oxidative stress inhibits distant metastasis by human melanoma cells
Piskounova, E., Agathocleous, M., Murphy, M. M., Hu, Z., Huddlestun, S. E., Zhao, Z., Leitch, A. M., Johnson, T. M., DeBerardinis, R. J., & Morrison, S. J. (2015) · Nature · doi:10.1038/nature15726 · Cited by 1,269 · see citing works
Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis
Locasale, J. W., Grassian, A. R., Melman, T., Lyssiotis, C. A., Mattaini, K. R., Bass, A. J., Heffron, G., Metallo, C. M., Muranen, T., Sharfi, H., et al. (2011) · Nature Genetics · doi:10.1038/ng.890 · Cited by 1,120 · see citing works
Quantitative flux analysis reveals folate-dependent NADPH production
Fan, J., Ye, J., Kamphorst, J. J., Shlomi, T., Thompson, C. B., & Rabinowitz, J. D. (2014) · Nature · doi:10.1038/nature13236 · Cited by 1,114 · see citing works
Self-citationmTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle
Ben-Sahra, I., Hoxhaj, G., Ricoult, S. J. H., Asara, J. M., & Manning, B. D. (2016) · Science · doi:10.1126/science.aad0489 · Cited by 795 · see citing works
NRF2 regulates serine biosynthesis in non–small cell lung cancer
DeNicola, G. M., Chen, P.-H., Mullarky, E., Sudderth, J., Hu, Z., Wu, D., Tang, H., Xie, Y., Asara, J. M., Huffman, K. E., et al. (2015) · Nature Genetics · doi:10.1038/ng.3421 · Cited by 747 · see citing works
Compartmentalization of Mammalian Folate-Mediated One-Carbon Metabolism
Tibbetts, A. S., & Appling, D. R. (2010) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.012809.104810 · Cited by 692 · cited 1× · see citing works
“We find, however, that, consistent with most prior literature on this topic, cytosolic 1C pathway fluxes in most proliferating cells are typically running in the direction from 10-formyl-THF to methylene-THF and therefore are consuming, not producing, NADPH (Tibbetts and Appling, 2010).”
Nilsson, R., Jain, M., Madhusudhan, N., Sheppard, N. G., Strittmatter, L., Kampf, C., Huang, J., Asplund, A., & Mootha, V. K. (2014) · Nature Communications · doi:10.1038/ncomms4128 · Cited by 607 · see citing works
Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells
Labuschagne, C. F., van den Broek, N. J. F., Mackay, G. M., Vousden, K. H., & Maddocks, O. D. K. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.04.045 · Cited by 576 · see citing works
Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells
Lewis, C. A., Parker, S. J., Fiske, B. P., McCloskey, D., Gui, D. Y., Green, C. R., Vokes, N. I., Feist, A. M., Vander Heiden, M. G., & Metallo, C. M. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.05.008 · Cited by 562 · see citing works
Lu, W., Clasquin, M. F., Melamud, E., Amador‐Noguez, D., Caudy, A. A., & Rabinowitz, J. D. (2010) · Analytical Chemistry · doi:10.1021/ac902837x · Cited by 504 · see citing works
Self-citationSerine Catabolism Regulates Mitochondrial Redox Control during Hypoxia
Ye, J., Fan, J., Venneti, S., Wan, Y.-W., Pawel, B. R., Zhang, J., Finley, L. W. S., Lu, C., Lindsten, T., Cross, J. R., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0250 · Cited by 452 · see citing works
Self-citationFan, J., Kamphorst, J. J., Mathew, R., Chung, M. K., White, E., Shlomi, T., & Rabinowitz, J. D. (2013) · Molecular Systems Biology · doi:10.1038/msb.2013.65 · Cited by 428 · see citing works
Self-citationSHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance
Kim, D., Fiske, B. P., Birsoy, K., Freinkman, E., Kami, K., Possemato, R. L., Chudnovsky, Y., Pacold, M. E., Chen, W. W., Cantor, J. R., et al. (2015) · Nature · doi:10.1038/nature14363 · Cited by 368 · see citing works
Herbig, K., Chiang, E. I., Lee, L.-R., Hills, J., Shane, B., & Stover, P. J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205000200 · Cited by 264 · see citing works
The methotrexate story: A paradigm for development of cancer chemotherapeutic agents
Huennekens, F. M. (1994) · Advances in Enzyme Regulation · doi:10.1016/0065-2571(94)90025-6 · Cited by 251 · see citing works
SHMT1 and SHMT2 Are Functionally Redundant in Nuclear De novo Thymidylate Biosynthesis
Anderson, D. D., & Stover, P. J. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005839 · Cited by 199 · see citing works
Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria
Anderson, D. D., Quintero, C. M., & Stover, P. J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1103623108 · Cited by 186 · see citing works
Tucker, E. J., Hershman, S. G., Köhrer, C., Belcher-Timme, C. A., Patel, J., Goldberger, O., Christodoulou, J., Silberstein, J. M., McKenzie, M., Ryan, M. T., et al. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.07.010 · Cited by 176 · see citing works
Comparative Oncogenomics Identifies PSMB4 and SHMT2 as Potential Cancer Driver Genes
Lee, G. Y., Haverty, P. M., Li, L., Kljavin, N. M., Bourgon, R., Lee, J., Stern, H. M., Modrusan, Z. D., Seshagiri, S., Zhang, Z., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-2683 · Cited by 162 · see citing works
Deletion of Mthfd1l causes embryonic lethality and neural tube and craniofacial defects in mice
Momb, J., Lewandowski, J. P., Bryant, J. D., Fitch, R. D., Surman, D. R., Vokes, S. A., & Appling, D. R. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1211199110 · Cited by 160 · see citing works
Stover, P. J., Chen, L. H., Suh, J. R., Stover, D. M., Keyomarsi, K., & Shane, B. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.3.1842 · Cited by 138 · see citing works
Self-citationPike, S., Rajendra, R., Artzt, K., & Appling, D. R. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.079855 · Cited by 120 · see citing works
Pietro, E. D., Sirois, J., Tremblay, M. L., & MacKenzie, R. E. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.12.4158-4166.2002 · Cited by 120 · see citing works
Fu, T.-F., Rife, J. P., & Schirch, V. (2001) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.2001.2471 · Cited by 72 · see citing works
Analysis of protein-coding genetic variation in 60,706 humans
Atzmon, Palotie, A. V., Ripke, S., Rivas, M. A., Won, H., Freimer, Lyon, Rodríguez-Guillén, Barr, Weisburd, B., et al. (2020) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · doi:10.17615/akst-av84 · Cited by 66 · see citing works
Patel, H., Pietro, E. D., & MacKenzie, R. E. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301718200 · Cited by 62 · see citing works
Bolusani, S., Young, B. A., Cole, N., Tibbetts, A. S., Momb, J., Bryant, J. D., Solmonson, A., & Appling, D. R. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.196840 · Cited by 58 · see citing works
An isotope-dilution, GC–MS assay for formate and its application to human and animal metabolism
Lamarre, S. G., MacMillan, L., Morrow, G. P., Randell, E. W., Pongnopparat, T., Brosnan, M. E., & Brosnan, J. T. (2014) · Amino Acids · doi:10.1007/s00726-014-1738-7 · Cited by 57 · see citing works
Division of labor in transhydrogenase by alternating proton translocation and hydride transfer
Leung, J. H., Schurig-Briccio, L. A., Yamaguchi, M., Moeller, A., Speir, J. A., Gennis, R. B., & Stout, C. D. (2015) · Science · doi:10.1126/science.1260451 · Cited by 48 · see citing works
Hanzlik, R. P., Fowler, S. C., & Eells, J. T. (2004) · Drug Metabolism and Disposition · doi:10.1124/dmd.104.001289 · Cited by 46 · see citing works
Pelletier, J. N., & MacKenzie, R. E. (1995) · Biochemistry · doi:10.1021/bi00039a025 · Cited by 39 · see citing works
Methods for Intravenous Self Administration in a Mouse Model
Kmiotek, E. K., Baimel, C., & Gill, K. J. (2012) · Journal of Visualized Experiments · doi:10.3791/3739 · Cited by 35 · see citing works
Species differences in methanol and formic acid pharmacokinetics in mice, rabbits and primates
Sweeting, J. N., Siu, M. T., McCallum, G. P., Miller, L., & Wells, P. G. (2010) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2010.05.009 · Cited by 24 · see citing works
Jägerstad, M., & Jastrebova, J. A. (2014) · Biomedical Chromatography · doi:10.1002/bmc.3214 · Cited by 12 · see citing works
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- World Health Organization 2008 The global burden of disease: 2004 update Geneva WHO Press
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One-Carbon Metabolism in Health and Disease
Ducker, G. S., & Rabinowitz, J. D. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2016.08.009 · Cited by 2,239 · see citing works
Self-citationThe multifaceted contributions of mitochondria to cellular metabolism
Spinelli, J. B., & Haigis, M. C. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0124-1 · Cited by 1,935 · see citing works
Cancer metabolism: looking forward
Martínez‐Reyes, I., & Chandel, N. S. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00378-6 · Cited by 1,852 · see citing works
Vyas, S., Zaganjor, E., & Haigis, M. C. (2016) · Cell · doi:10.1016/j.cell.2016.07.002 · Cited by 1,735 · see citing works
Circadian physiology of metabolism
Panda, S. (2016) · Science · doi:10.1126/science.aah4967 · Cited by 1,092 · see citing works
Targeting Metabolism for Cancer Therapy
Luengo, A., Gui, D. Y., & Vander Heiden, M. G. (2017) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.08.028 · Cited by 971 · see citing works
Serine and one-carbon metabolism in cancer
Yang, M., & Vousden, K. H. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.81 · Cited by 992 · see citing works
Metabolomics and Isotope Tracing
Jang, C., Chen, L., & Rabinowitz, J. D. (2018) · Cell · doi:10.1016/j.cell.2018.03.055 · Cited by 841 · see citing works
Self-citationNADPH homeostasis in cancer: functions, mechanisms and therapeutic implications
Ju, H., Lin, J., Tian, T., Xie, D., & Xu, R. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00326-0 · Cited by 595 · see citing works
A New View into the Regulation of Purine Metabolism: The Purinosome
Pedley, A. M., & Benkovic, S. J. (2016) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2016.09.009 · Cited by 580 · see citing works
One-carbon metabolism in cancer
Newman, A. C., & Maddocks, O. D. K. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.118 · Cited by 509 · see citing works
Vitamin B 12 , folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation
Froese, D. S., Fowler, B., & Baumgartner, M. R. (2019) · Journal of Inherited Metabolic Disease · doi:10.1002/jimd.12009 · Cited by 479 · see citing works
Mitochondrial Biogenesis and Proteome Remodeling Promote One-Carbon Metabolism for T Cell Activation
Ron-Harel, N., Santos, D., Ghergurovich, J. M., Sage, P. T., Reddy, A., Lovitch, S. B., Dephoure, N., Satterstrom, F. K., Sheffer, M., Spinelli, J. B., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.06.007 · Cited by 429 · see citing works
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Mattaini, K. R., Sullivan, M. R., & Heiden, M. G. V. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.201604085 · Cited by 409 · see citing works
Guo, J. Y., Teng, X., Laddha, S. V., Ma, S., Nostrand, S. C. V., Yang, Y., Khor, S., Chan, C. S., Rabinowitz, J. D., & White, E. (2016) · Genes & Development · doi:10.1101/gad.283416.116 · Cited by 373 · see citing works
Self-citationMammals divert endogenous genotoxic formaldehyde into one-carbon metabolism
Burgos-Barragan, G., Wit, N., Meiser, J., Dingler, F. A., Pietzke, M., Mulderrig, L., Pontel, L. B., Rosado, I. V., Brewer, T. F., Cordell, R. L., et al. (2017) · Nature · doi:10.1038/nature23481 · Cited by 359 · see citing works
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Rodriguez, A. E., Ducker, G. S., Billingham, L. K., Martinez, C. A., Mainolfi, N., Suri, V., Friedman, A. A., Manfredi, M. G., Weinberg, S. E., Rabinowitz, J. D., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.01.014 · Cited by 346 · see citing works
Self-citationMitochondrial translation requires folate-dependent tRNA methylation
Morscher, R. J., Ducker, G. S., Li, H., Mayer, J., Gitai, Z., Sperl, W., & Rabinowitz, J. D. (2018) · Nature · doi:10.1038/nature25460 · Cited by 278 · see citing works
Self-citationRegulation of Stem Cell Aging by Metabolism and Epigenetics
Ren, R., Ocampo, A., Liu, G., & Belmonte, J. C. I. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.07.019 · Cited by 269 · see citing works
Ducker, G. S., Ghergurovich, J. M., Mainolfi, N., Suri, V., Jeong, S. K., Hsin-Jung Li, S., Friedman, A., Manfredi, M. G., Gitai, Z., Kim, H., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1706617114 · Cited by 261 · see citing works
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Kory, N., Wyant, G. A., Prakash, G., de Bos, J. U., Bottanelli, F., Pacold, M. E., Chan, S. H., Lewis, C. A., Wang, T., Keys, H. R., et al. (2018) · Science · doi:10.1126/science.aat9528 · Cited by 246 · see citing works
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Pan, S., Fan, M., Liu, Z., Li, X., & Wang, H. (2020) · International Journal of Oncology · doi:10.3892/ijo.2020.5158 · Cited by 227 · see citing works
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Sugiura, A., Andrejeva, G., Voss, K., Heintzman, D. R., Xu, X., Madden, M. Z., Ye, X., Beier, K. L., Chowdhury, N. U., Wolf, M. M., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.10.011 · Cited by 219 · see citing works
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van der Knaap, J. A., & Verrijzer, C. P. (2016) · Genes & Development · doi:10.1101/gad.289140.116 · Cited by 213 · see citing works
The Diverse Functions of Non-Essential Amino Acids in Cancer
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MCART1/SLC25A51 is required for mitochondrial NAD transport
Kory, N., uit de Bos, J., van der Rijt, S., Jankovic, N., Güra, M., Arp, N., Pena, I. A., Prakash, G., Chan, S. H., Kunchok, T., et al. (2020) · Science Advances · doi:10.1126/sciadv.abe5310 · Cited by 205 · see citing works
Rose, J., Brian, C., Pappa, A., Panayiotidis, M. I., & Franco, R. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.536682 · Cited by 196 · see citing works
Ju, H., Lu, Y., Chen, D.-L., Zuo, Z.-X., Liu, Z., Wu, Q.-N., Mo, H., Wang, Z., Wang, D., Pu, H., et al. (2018) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djy160 · Cited by 189 · see citing works
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Liu, X., Zhang, Y., Zhuang, L., Olszewski, K. L., & Gan, B. (2020) · Genes & Diseases · doi:10.1016/j.gendis.2020.11.010 · Cited by 184 · see citing works
Mitochondrial NADP(H) generation is essential for proline biosynthesis
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Emerging strategies for treating metastasis
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Transforming Growth Factor (TGF)-β Promotes de Novo Serine Synthesis for Collagen Production
Nigdelioglu, R., Hamanaka, R. B., Meliton, A. Y., O'Leary, E., Witt, L. J., Cho, T., Sun, K., Bonham, C., Wu, D., Woods, P. S., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.756247 · Cited by 169 · see citing works
Selvarajah, B., Azuelos, I., Platé, M., Guillotin, D., Forty, E. J., Contento, G., Woodcock, H. V., Redding, M., Taylor, A. R., Brunori, G., et al. (2019) · Science Signaling · doi:10.1126/scisignal.aav3048 · Cited by 174 · see citing works
Serine and Functional Metabolites in Cancer
Newman, A. C., & Maddocks, O. D. K. (2017) · Trends in Cell Biology · doi:10.1016/j.tcb.2017.05.001 · Cited by 168 · see citing works
Glutathione and its precursors in cancer
Asantewaa, G., & Harris, I. S. (2021) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2021.03.001 · Cited by 158 · see citing works
Diehl, F. F., Lewis, C. A., Fiske, B. P., & Vander Heiden, M. G. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0108-x · Cited by 159 · see citing works
Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma
Lee, D., Xu, M., Chiu, D. K., Lai, R. K., Tse, A. P., Li, L. L., Law, C., Tsang, F. H., Wei, L. L., Chan, C. Y., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90253 · Cited by 152 · see citing works
Frigerio, B., Bizzoni, C., Jansen, G., Leamon, C. P., Peters, G. J., Low, P. S., Matherly, L. H., & Figini, M. (2019) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-019-1123-1 · Cited by 146 · see citing works
Defective NADPH production in mitochondrial disease complex I causes inflammation and cell death
Balsa, E., Perry, E. A., Bennett, C. F., Jedrychowski, M. P., Gygi, S. P., Doench, J. G., & Puigserver, P. (2020) · Nature Communications · doi:10.1038/s41467-020-16423-1 · Cited by 138 · see citing works
Ohata, J., Bruemmer, K. J., & Chang, C. J. (2019) · Accounts of Chemical Research · doi:10.1021/acs.accounts.9b00386 · Cited by 135 · see citing works
Glycolytic Metabolism, Brain Resilience, and Alzheimer’s Disease
Zhang, X., Alshakhshir, N., & Zhao, L. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.662242 · Cited by 134 · see citing works
A genetically encoded tool for manipulation of NADP+/NADPH in living cells
Cracan, V., Titov, D. V., Shen, H., Grabarek, Z., & Mootha, V. K. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2454 · Cited by 132 · see citing works
SHMT inhibition is effective and synergizes with methotrexate in T-cell acute lymphoblastic leukemia
García‐Cañaveras, J. C., Lancho, O., Ducker, G. S., Ghergurovich, J. M., Xu, X., da Silva-Diz, V., Minuzzo, S. A., Indraccolo, S., Kim, H., Herranz, D., et al. (2020) · Leukemia · doi:10.1038/s41375-020-0845-6 · Cited by 129 · see citing works
Self-citationNuclear metabolism and the regulation of the epigenome
Boon, R., da Silveira, G. G., & Mostoslavsky, R. (2020) · Nature Metabolism · doi:10.1038/s42255-020-00285-4 · Cited by 125 · see citing works
Role of mitochondria in liver metabolic health and diseases
Morio, B., Panthu, B., Bassot, A., & Rieusset, J. (2020) · Cell Calcium · doi:10.1016/j.ceca.2020.102336 · Cited by 130 · see citing works
Reprogramming of serine, glycine and one-carbon metabolism in cancer
Li, A. M., & Ye, J. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.165841 · Cited by 127 · see citing works
Serine catabolism generates liver NADPH and supports hepatic lipogenesis
Zhang, Z., TeSlaa, T. A., Xu, X., Zeng, X., Yang, L., Xing, G., Tesz, G. J., Clasquin, M. F., & Rabinowitz, J. D. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00487-4 · Cited by 126 · see citing works
Self-citationThe complexity of the serine glycine one-carbon pathway in cancer
Reina‐Campos, M., Díaz-Meco, M. T., & Moscat, J. (2019) · The Journal of Cell Biology · doi:10.1083/jcb.201907022 · Cited by 123 · see citing works
An Epigenetic Role of Mitochondria in Cancer
Liu, Y., Chen, C., Wang, X., Sun, Y., Zhang, J., Chen, J., & Shi, Y. (2022) · Cells · doi:10.3390/cells11162518 · Cited by 125 · see citing works
Increased formate overflow is a hallmark of oxidative cancer
Meiser, J., Schuster, A. M., Pietzke, M., Voorde, J. V., Athineos, D., Oizel, K., Burgos-Barragan, G., Wit, N., Dhayade, S., Morton, J. P., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03777-w · Cited by 119 · see citing works
Folate metabolism: a re-emerging therapeutic target in haematological cancers
Zarou, M. M., Vázquez, A., & Helgason, G. V. (2021) · Leukemia · doi:10.1038/s41375-021-01189-2 · Cited by 120 · see citing works
Metabolic Regulation of Redox Balance in Cancer
Purohit, V., Simeone, D. M., & Lyssiotis, C. A. (2019) · Cancers · doi:10.3390/cancers11070955 · Cited by 115 · see citing works
MTHFD2 links RNA methylation to metabolic reprogramming in renal cell carcinoma
Green, N. H., Galvan, D. L., Badal, S. S., Chang, B. H., LeBleu, V. S., Long, J., Jonasch, E., & Danesh, F. R. (2019) · Oncogene · doi:10.1038/s41388-019-0869-4 · Cited by 117 · see citing works
Jain, A., & Zoncu, R. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101481 · Cited by 116 · see citing works
Nishimura, T., Nakata, A., Chen, X., Nishi, K., Meguro‐Horike, M., Sasaki, S., Kita, K., Horike, S., Saitoh, K., Kato, K., et al. (2018) · Oncogene · doi:10.1038/s41388-018-0589-1 · Cited by 112 · see citing works
Vučetić, M., Cormerais, Y., Parks, S. K., & Pouysségur, J. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00319 · Cited by 113 · see citing works
Newman, A. C., Falcone, M., Uribe, A. H., Zhang, T., Athineos, D., Pietzke, M., Vázquez, A., Blyth, K., & Maddocks, O. D. K. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.03.019 · Cited by 111 · see citing works
Beyond the Warburg effect: How do cancer cells regulate one-carbon metabolism?
Rosenzweig, A., Blenis, J., & Gomes, A. P. (2018) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2018.00090 · Cited by 107 · see citing works
GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency
Guerrero, J. A., Klysz, D. D., Chen, Y., Malipatlolla, M. B., Lone, J. B., Fowler, C., Stuani, L., May, A., Bashti, M., Xu, P., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-52666-y · Cited by 108 · see citing works
More than a metabolic enzyme: MTHFD2 as a novel target for anticancer therapy?
Zhu, Z., & Leung, G. K. K. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00658 · Cited by 106 · see citing works
Mitochondrial One-Carbon Pathway Supports Cytosolic Folate Integrity in Cancer Cells
Zheng, Y., Lin, T.-Y., Lee, G., Paddock, M. N., Momb, J., Cheng, Z., Li, Q., Fei, D. L., Stein, B. D., Ramsamooj, S., et al. (2018) · Cell · doi:10.1016/j.cell.2018.09.041 · Cited by 106 · see citing works
Role of the ISR-ATF4 pathway and its cross talk with Nrf2 in mitochondrial quality control
Kasai, S., Yamazaki, H., Tanji, K., Engler, M. J., Matsumiya, T., & Itoh, K. (2018) · Journal of Clinical Biochemistry and Nutrition · doi:10.3164/jcbn.18-37 · Cited by 101 · see citing works
Robinson, A. D., Eich, M., & Varambally, S. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.11.013 · Cited by 104 · see citing works
Pranzini, E., Pardella, E., Muccillo, L., Leo, A., Nesi, I., Santi, A., Parri, M., Zhang, T., Uribe, A. H., Lottini, T., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111233 · Cited by 105 · see citing works
Fujihara, K. M., Zhang, B. Z., Jackson, T. D., Ogunkola, M. O., Nijagal, B., Milne, J. V., Sallman, D. A., Ang, C.-S., Nikolic, I., Kearney, C. J., et al. (2022) · Science Advances · doi:10.1126/sciadv.abm9427 · Cited by 103 · see citing works
Regulatory mechanisms of one-carbon metabolism enzymes
Petrova, B., Maynard, A. G., Wang, P., & Kanarek, N. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.105457 · Cited by 103 · see citing works
Bonagas, N., Gustafsson, N., Henriksson, M., Marttila, P., Gustafsson, R., Wiita, E., Borhade, S. R., Green, A. C., Vallin, K. S. A., Sarno, A., et al. (2022) · Nature Cancer · doi:10.1038/s43018-022-00331-y · Cited by 101 · see citing works
Chemical Basis for Deuterium Labeling of Fat and NADPH
Zhang, Z., Chen, L., Лиу, Л., Su, X., & Rabinowitz, J. D. (2017) · Journal of the American Chemical Society · doi:10.1021/jacs.7b08012 · Cited by 94 · see citing works
Self-citationKawai, J., Toki, T., Ota, M., Inoue, H., Takata, Y., Asahi, T., Suzuki, M., Shimada, T., Ono, K., Suzuki, K., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01113 · Cited by 94 · see citing works
Metabolic determination of cell fate through selective inheritance of mitochondria
Döhla, J., Kuuluvainen, E., Gebert, N., Amaral, A. I., Englund, J. I., Gopalakrishnan, S., Konovalova, S. A., Nieminen, A. I., Salminen, E. S., Torregrosa‐Muñumer, R., et al. (2022) · Nature Cell Biology · doi:10.1038/s41556-021-00837-0 · Cited by 95 · see citing works
Liu, X., Mei, W., Padmanaban, V., Alwaseem, H., Molina, H., Passarelli, M. C., Tavora, B., & Tavazoie, S. F. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.05.008 · Cited by 96 · see citing works
Stable Isotopes for Tracing Mammalian-Cell Metabolism In Vivo
Fernández-García, J., Altea‐Manzano, P., Pranzini, E., & Fendt, S. (2020) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2019.12.002 · Cited by 94 · see citing works
Lozoya, O. A., Martínez‐Reyes, I., Wang, T., Grenet, D., Bushel, P. R., Li, J., Chandel, N. S., Woychik, R. P., & Santos, J. H. (2018) · PLoS Biology · doi:10.1371/journal.pbio.2005707 · Cited by 93 · see citing works
Mitochondrial and metabolic alterations in cancer cells
Gregorio, J. D., Petricca, S., Iorio, R., Toniato, E., & Flati, V. (2022) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2022.151225 · Cited by 93 · see citing works
The toxic side of one-carbon metabolism and epigenetics
Morellato, A. E., Umansky, C., & Pontel, L. B. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101850 · Cited by 92 · see citing works
Reich, S., Nguyen, C. D. L., Has, C., Steltgens, S., Soni, H., Coman, C., Freyberg, M., Bichler, A., Seifert, N., Conrad, D., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16747-y · Cited by 90 · see citing works
Reduced nicotinamide adenine dinucleotide phosphate in redox balance and diseases: a friend or foe?
Koju, N., Qin, Z., & Sheng, R. (2022) · Acta Pharmacologica Sinica · doi:10.1038/s41401-021-00838-7 · Cited by 95 · see citing works
Badolia, R., Ramadurai, D. K. A., Abel, E. D., Ferrin, P. C., Taleb, I., Shankar, T. S., Krokidi, A. T., Navankasattusas, S., McKellar, S. H., Yin, M. T., et al. (2020) · Circulation · doi:10.1161/circulationaha.119.044452 · Cited by 87 · see citing works
Li, A. M., Ducker, G. S., Li, Y., Seoane, J. A., Xiao, Y., Melemenidis, S., Zhou, Y., Liu, L., Vanharanta, S., Graves, E. E., et al. (2020) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-19-0606 · Cited by 84 · see citing works
Self-citationGeeraerts, S. L., Kampen, K. R., Rinaldi, G., Gupta, P., Planque, M., Louros, N. N., Heylen, E., Cremer, K. D., Brucker, K. D., Vereecke, S., et al. (2020) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-0480 · Cited by 85 · see citing works
Gorelova, V., Lepeleire, J. D., Daele, J. V., Pluim, D., Meï, C., Cuypers, A., Leroux, O., Rébeillé, F., Schellens, J. H. M., Blancquaert, D., et al. (2017) · The Plant Cell · doi:10.1105/tpc.17.00433 · Cited by 85 · see citing works
García‐Bermúdez, J., Badgley, M. A., Prasad, S., Baudrier, L., Liu, Y., La, K., Soula, M., Williams, R. T., Yamaguchi, N., Hwang, R. F., et al. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00583-z · Cited by 84 · see citing works
Metabolic pathway analysis using stable isotopes in patients with cancer
Bartman, C., Faubert, B., Rabinowitz, J. D., & DeBerardinis, R. J. (2023) · Nature reviews. Cancer · doi:10.1038/s41568-023-00632-z · Cited by 87 · see citing works
Self-citationEmerging evidence for targeting mitochondrial metabolic dysfunction in cancer therapy
Zhu, Y., Dean, A. E., Horikoshi, N., Heer, C. D., Spitz, D. R., & Gius, D. R. (2018) · Journal of Clinical Investigation · doi:10.1172/jci120844 · Cited by 78 · see citing works
p53 deficiency induces MTHFD2 transcription to promote cell proliferation and restrain DNA damage
Li, G. L., Wu, J., Li, L., & Jiang, P. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2019822118 · Cited by 78 · see citing works
Therapeutic Targeting of Mitochondrial One-Carbon Metabolism in Cancer
Dekhne, A. S., Hou, Z., Gangjee, A., & Matherly, L. H. (2020) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-0423 · Cited by 79 · see citing works
Targeting serine-glycine-one-carbon metabolism as a vulnerability in cancers
Sun, W. Y., Liu, R., Gao, X., Lin, Z., Tang, H., Cui, H., & Zhao, E. (2023) · Biomarker Research · doi:10.1186/s40364-023-00487-4 · Cited by 82 · see citing works
Mitochondria: The metabolic switch of cellular oncogenic transformation
Tan, Y. Q., Zhang, X., Zhang, S., Zhu, T., Garg, M., Lobie, P. E., & Pandey, V. (2021) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2021.188534 · Cited by 75 · see citing works
Sulfur metabolism and its contribution to malignancy
Ward, N. P., & DeNicola, G. M. (2019) · International review of cytology · doi:10.1016/bs.ircmb.2019.05.001 · Cited by 74 · see citing works
Hernández-Baixauli, J., Quesada‐Vázquez, S., Mariné-Casadó, R., Cardoso, K. G., Caimari, A., Bas-Prior, J. M. D., Escoté, X., & Baselga‐Escudero, L. (2020) · Nutrients · doi:10.3390/nu12030806 · Cited by 73 · see citing works
- Authors
- Ducker, G. S., Chen, L., Morscher, R. J., Ghergurovich, J. M., Esposito, M., Teng, X., Kang, Y., & Rabinowitz, J. D.
- Affiliations
- Princeton University (US)
- Innsbruck Medical University (AT)
- Corresponding author
- Rabinowitz, Joshua D.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 23
- Issue
- 6
- Pages
- 1140-1153
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4909566
- OpenAlex
- W2405069786
- Cited by
- 419
- References
- 41
- Citations by year
- 2026: 29 · 2025: 48 · 2024: 48 · 2023: 47 · 2022: 50 · 2021: 41 · 2020: 45 · 2019: 40 · 2018: 35 · 2017: 21 · 2016: 15
- FWCI
- 39.37
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-10-11)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by-nc-nd)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- US National Institutes of Health (R01CA16359-01A1)
- Stand Up to Cancer (SU2C-AACR-DT0509)
- Brewster Foundation
- NIH (R01CA141062, F31CA192461)
- US Department of Defense (BC123187)
- American Cancer Society (PF-15-190-01- TBE)
- NJCCR postdoctoral fellowship (DFHS15PPC044)
- PMU-FFF fellowship (L-15/03/004-MOR)
- Topics
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- one-carbon metabolism, serine catabolism, glutathione synthesis, glycine, CRISPR knockout, tumor cell proliferation, colon cancer xenografts, tumor growth
- MeSH terms
- Aminoimidazole Carboxamide, Carbon, Cell Compartmentation, Leucovorin, Colonic Neoplasms, Cytosol, Folic Acid, Formates, Glycine, Humans, Methylenetetrahydrofolate Dehydrogenase (NADP), Mitochondria, Mutation, NADP, Ribonucleotides, Serine, Glycine Hydroxymethyltransferase, Gene Library, Xenograft Model Antitumor Assays, HCT116 Cells, Cell Proliferation, Metabolic Networks and Pathways, Gene Knockout Techniques, HEK293 Cells, CRISPR-Cas Systems
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