The folate-coupled enzyme MTHFD2 is a nuclear protein and promotes cell proliferation
Open accessAbstract
Folate metabolism is central to cell proliferation and a target of commonly used cancer chemotherapeutics. In particular, the mitochondrial folate-coupled metabolism is thought to be important for proliferating cancer cells. The enzyme MTHFD2 in this pathway is highly expressed in human tumors and broadly required for survival of cancer cells. Although the enzymatic activity of the MTHFD2 protein is well understood, little is known about its larger role in cancer cell biology. We here report that MTHFD2 is co-expressed with two distinct gene sets, representing amino acid metabolism and cell proliferation, respectively. Consistent with a role for MTHFD2 in cell proliferation, MTHFD2 expression was repressed in cells rendered quiescent by deprivation of growth signals (serum) and rapidly re-induced by serum stimulation. Overexpression of MTHFD2 alone was sufficient to promote cell proliferation independent of its dehydrogenase activity, even during growth restriction. In addition to its known mitochondrial localization, we found MTHFD2 to have a nuclear localization and co-localize with DNA replication sites. These findings suggest a previously unknown role for MTHFD2 in cancer cell proliferation, adding to its known function in mitochondrial folate metabolism.
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Overexpression of MTHFD2 with an active site residue mutated that is required for catalysis still had a proliferative advantage compared to the vector control.
“Overexpression of MTHFD2 with an active site residue mutated that is required for catalysis still had a proliferative advantage compared to the vector control.”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [193]
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Cites
Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590 · see citing works
Dignam, J. D., Lebovitz, R. M., & Roeder, R. G. (1983) · Nucleic Acids Research · doi:10.1093/nar/11.5.1475 · Cited by 11,262 · see citing works
NCBI GEO: archive for functional genomics data sets—update
Barrett, T., Wilhite, S. E., Ledoux, P., Evangelista, C., Kim, I. F., Tomashevsky, M., Marshall, K. A., Phillippy, K. H., Sherman, P. M., Holko, M., et al. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks1193 · Cited by 10,418 · see citing works
CellProfiler: image analysis software for identifying and quantifying cell phenotypes
Carpenter, A. E., Jones, T. R., Lamprecht, M. R., Clarke, C., Kang, I. H., Friman, O., Guertin, D. A., Chang, J. H., Lindquist, R. A., Moffat, J., et al. (2006) · Genome biology · doi:10.1186/gb-2006-7-10-r100 · Cited by 5,077 · see citing works
Regulation of cancer cell metabolism
Cairns, R. A., Harris, I. S., & Mak, T. W. (2011) · Nature Reviews Cancer · doi:10.1038/nrc2981 · Cited by 4,744 · 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
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
Nuclear structure in cancer cells
Zink, D., Fischer, A. H., & Nickerson, J. A. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1430 · Cited by 1,070 · see citing works
Leptomycin B Inhibition of Signal-Mediated Nuclear Export by Direct Binding to CRM1
Kudo, N. R., Wolff, B., Sekimoto, T., Schreiner, E. P., Yoneda, Y., Yanagida, M., Horinouchi, S., & Yoshida, M. (1998) · Experimental Cell Research · doi:10.1006/excr.1998.4136 · Cited by 812 · 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 · see citing works
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
ATF4-dependent transcription mediates signaling of amino acid limitation
Kilberg, M. S., Shan, J., & Su, N. Y. (2009) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2009.05.008 · Cited by 595 · see citing works
The Mouse Genome Database: integration of and access to knowledge about the laboratory mouse
Blake, J. A., Bult, C. J., Eppig, J. T., Kadin, J. A., Richardson, J. E., & The Mouse Genome Database Group (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt1225 · Cited by 210 · see citing works
How do glycolytic enzymes favour cancer cell proliferation by nonmetabolic functions?
Lincet, H., & Icard, P. (2014) · Oncogene · doi:10.1038/onc.2014.320 · Cited by 207 · 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
Selçuklu, S. D., Donoghue, M. T. A., Rehmet, K., Gomes, M. D. S., Fort, A., Kovvuru, P., Muniyappa, M. K., Kerin, M. J., Enright, A. J., & Spillane, C. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.335943 · Cited by 179 · see citing works
The Transcription Factor Network Associated With the Amino Acid Response in Mammalian Cells
Kilberg, M. S., Balasubramanian, M. N., Fu, L., & Shan, J. (2012) · Advances in Nutrition · doi:10.3945/an.112.001891 · Cited by 143 · see citing works
Trafficking of Intracellular Folates
Stover, P. J., & Field, M. S. (2011) · Advances in Nutrition · doi:10.3945/an.111.000596 · Cited by 135 · see citing works
Barlowe, C. K., & Appling, D. R. (1988) · PubMed · Cited by 110 · see citing works
Lehtinen, L., Ketola, K., Mäkelä, R., Mpindi, J.-P., Viitala, M., Kallioniemi, O., & Iljin, K. (2012) · Oncotarget · doi:10.18632/oncotarget.756 · Cited by 109 · see citing works
NAD-dependent methylenetetrahydrofolate dehydrogenase is expressed by immortal cells.
Mejia, N. R., & MacKenzie, R. E. (1985) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)38612-x · Cited by 97 · see citing works
Field, M. S., Kamynina, E., Agunloye, O. C., Liebenthal, R. P., Lamarre, S. G., Brosnan, M. E., Brosnan, J. T., & Stover, P. J. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.599589 · Cited by 77 · see citing works
Lund, R., Aittokallio, T. A., Nevalainen, O., & Lahesmaa, R. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.10.5328 · Cited by 76 · see citing works
The Effect of Mitochondrial Dysfunction on Cytosolic Nucleotide Metabolism
Desler, C., Lykke, A., & Rasmussen, L. J. (2010) · Journal of Nucleic Acids · doi:10.4061/2010/701518 · Cited by 70 · 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
Mejia, N. R., & MacKenzie, R. E. (1988) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(88)81040-4 · Cited by 58 · see citing works
Modeling cellular compartmentation in one‐carbon metabolism
Scotti, M., Stella, L., Shearer, E. J., & Stover, P. J. (2013) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1209 · Cited by 46 · see citing works
Christensen, K. E., Mirza, I. A., Berghuis, A. M., & MacKenzie, R. E. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m505210200 · Cited by 37 · see citing works
Voets, A. M., Lindsey, P. J., Vanherle, S. J. V., Timmer, E. D. J., Esseling, J. J., Koopman, W. J. H., Willems, P. H. G. M., Schoonderwoerd, G. C., Groote, D. D., Poll‐The, B. T., et al. (2012) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2012.07.001 · Cited by 27 · see citing works
Rathi, A. V., Robles, M. T. S., & Pipas, J. M. (2007) · Journal of Virology · doi:10.1128/jvi.00922-07 · Cited by 13 · see citing works
Erratum: Corrigendum: 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/nature13675 · Cited by 10 · see citing works
Patel, H., Pietro, E. D., Mejia, N. R., & MacKenzie, R. E. (2005) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2005.07.022 · Cited by 8 · see citing works
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- Field M. S.. Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency. J Biol Chem 289, 29642– 29650, 10.1074/jbc.M114.599589 (2014). 25213861 PMC4207979 · DOI
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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
MTHFD2 is a metabolic checkpoint controlling effector and regulatory T cell fate and function
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
One-carbon metabolism and nucleotide biosynthesis as attractive targets for anticancer therapy
Shuvalov, O., Petukhov, A., Daks, A., Fedorova, O., Vasileva, E., & Barlev, N. A. (2017) · Oncotarget · doi:10.18632/oncotarget.15053 · Cited by 168 · 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
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
Folate-mediated one-carbon metabolism: a targeting strategy in cancer therapy
Yang, C., Zhang, J., Liao, M., Yang, Y., Wang, Y., Yuan, Y., & Ouyang, L. (2020) · Drug Discovery Today · doi:10.1016/j.drudis.2020.12.006 · Cited by 126 · 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
Formate: The Neglected Member of One-Carbon Metabolism
Brosnan, M. E., & Brosnan, J. T. (2016) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071715-050738 · Cited by 113 · see citing works
Cell cycle regulation of folate‐mediated one‐carbon metabolism
Lan, X., Field, M. S., & Stover, P. J. (2018) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1426 · Cited by 113 · 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
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
Interpreting pathways to discover cancer driver genes with Moonlight
Colaprico, A., Olsen, C., Bailey, M. H., Odom, G., Terkelsen, T., Silva, T. C., Olsen, A. V., Cantini, L., Zinovyev, A. Y., Barillot, E., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-13803-0 · Cited by 100 · see citing works
Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor
Gustafsson, R., Jemth, A., Gustafsson, N., Färnegårdh, K., Loseva, O., Wiita, E., Bonagas, N., Dahllund, L., Llona‐Minguez, S., Häggblad, M., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-1476 · Cited by 97 · see citing works
NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview
Pramono, A. A., Rather, G. M., Herman, H., Lestari, K., & Bertino, J. R. (2020) · Biomolecules · doi:10.3390/biom10030358 · Cited by 88 · see citing works
Field, M. S., Kamynina, E., Chon, J., & Stover, P. J. (2018) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071714-034441 · Cited by 85 · 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
Snaebjornsson, M. T., & Schulze, A. (2018) · Experimental & Molecular Medicine · doi:10.1038/s12276-018-0065-6 · Cited by 77 · see citing works
Therapeutic targeting of the mitochondrial one-carbon pathway: perspectives, pitfalls, and potential
Zhao, L. N., Björklund, M., Caldez, M. J., Zheng, J., & Kaldis, P. (2021) · Oncogene · doi:10.1038/s41388-021-01695-8 · Cited by 70 · see citing works
ALDH1L1 and ALDH1L2 Folate Regulatory Enzymes in Cancer
Krupenko, S. A., & Krupenko, N. I. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-98788-0_10 · Cited by 63 · see citing works
A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight
Cuthbertson, C. R., Arabzada, Z., Bankhead, A., Kyani, A., & Neamati, N. (2021) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.0c00223 · Cited by 57 · see citing works
Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells
Green, A. C., Marttila, P., Kiweler, N., Chalkiadaki, C., Wiita, E., Cookson, V. J., Lesur, A., Eiden, K., Bernardin, F., Vallin, K. S. A., et al. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00771-5 · Cited by 56 · see citing works
Cysteine as a Carbon Source, a Hot Spot in Cancer Cells Survival
Serpa, J. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00947 · Cited by 53 · see citing works
Basalova, N. A., Mikhail, A., Vladimir, P., Olga, G., Maksim, V., Ivan, Z., Novoseletskaya, E. S., Sagaradze, G. D., Natalia, D., Pavel, M., et al. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01017-w · Cited by 55 · see citing works
Yue, L., Pei, Y., Zhong, L., Yang, H. H., Wang, Y., Zhang, W., Chen, N., Zhu, Q., Gao, J., Zhi, M., et al. (2020) · Stem Cell Reports · doi:10.1016/j.stemcr.2020.06.018 · Cited by 50 · see citing works
Targeting the DNA damage response and repair in cancer through nucleotide metabolism
Helleday, T., & Rudd, S. G. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13227 · Cited by 48 · see citing works
Koufaris, C., Gallage, S., Yang, T., Lau, C. E., Valbuena, G. N., & Keun, H. C. (2016) · Journal of Proteome Research · doi:10.1021/acs.jproteome.6b00188 · Cited by 48 · see citing works
Koufaris, C., & Nilsson, R. (2018) · Cancer & Metabolism · doi:10.1186/s40170-018-0185-4 · Cited by 44 · see citing works
MTHFD2 facilitates breast cancer cell proliferation via the AKT signaling pathway
Huang, J., Qin, Y., Lin, C., Huang, X., & Zhang, F. (2021) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2021.10135 · Cited by 45 · see citing works
Long, N. P., Jung, K. H., Yoon, S. J., Anh, N. H., Nghi, T. D., Kang, Y. P., YAN, H. H., Min, J. E., Hong, S., & Kwon, S. W. (2017) · Oncotarget · doi:10.18632/oncotarget.22689 · Cited by 45 · see citing works
Targeting MTHFD2 to Exploit Cancer-Specific Metabolism and the DNA Damage Response
Ramos, L., Henriksson, M., Helleday, T., & Green, A. C. (2023) · Cancer Research · doi:10.1158/0008-5472.can-23-1290 · Cited by 38 · see citing works
Mitochondrial MTHFD isozymes display distinct expression, regulation, and association with cancer
Nilsson, R., Nicolaidou, V., & Koufaris, C. (2019) · Gene · doi:10.1016/j.gene.2019.144032 · Cited by 36 · see citing works
One carbon metabolism in human lung cancer
Yao, S., Peng, L., Elakad, O., Küffer, S., Hinterthaner, M., Danner, B. C., von Hammerstein-Equord, A. F., Ströbel, P., & Bohnenberger, H. (2021) · Translational Lung Cancer Research · doi:10.21037/tlcr-20-1039 · Cited by 36 · see citing works
Achreja, A., Yu, T., Mittal, A., Choppara, S., Animasahun, O. H., Nenwani, M., Wuchu, F., Meurs, N., Mohan, A., Jeon, J. H., et al. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00636-3 · Cited by 36 · see citing works
MTHFD2 reprograms macrophage polarization by inhibiting PTEN
Shang, M., Ni, L., Shan, X., Cui, Y., Hu, P., Ji, Z., Shen, L., Zhang, Y., Zhou, J., Chen, B., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112481 · Cited by 34 · see citing works
Metabolite Profiling and Stable Isotope Tracing in Sorted Subpopulations of Mammalian Cells
Roçi, I., Gallart‐Ayala, H., Schmidt, A., Watrous, J. D., Jain, M., Wheelock, C. E., & Nilsson, R. (2016) · Analytical Chemistry · doi:10.1021/acs.analchem.5b04071 · Cited by 34 · see citing works
Mo, J., Gao, Z., Li, Z., Yan, M., Xue, M., Xu, J., Bao, Y., & Wu, J. (2022) · Cell Death Discovery · doi:10.1038/s41420-022-01098-y · Cited by 33 · see citing works
Metabolic modulation of transcription: The role of one-carbon metabolism
Lin, J.-M. G., Kourtis, S., Ghose, R., Lorente, N. P., Kubicek, S., & Sdelci, S. (2022) · Cell chemical biology · doi:10.1016/j.chembiol.2022.11.009 · Cited by 35 · see citing works
MTHFD2 promotes ovarian cancer growth and metastasis via activation of the STAT3 signaling pathway
Li, Q., Yang, F., Shi, X., Bian, S., Shen, F., Wu, Y., Zhu, C., Fu, F., Wang, J., Zhou, J., et al. (2021) · FEBS Open Bio · doi:10.1002/2211-5463.13249 · Cited by 32 · see citing works
Non‐metabolic function of MTHFD2 activates CDK2 in bladder cancer
Liu, X., Liu, S., Piao, C., Zhang, Z., Zhang, X., Jiang, Y., & Kong, C. (2021) · Cancer Science · doi:10.1111/cas.15159 · Cited by 32 · see citing works
Folate enzyme MTHFD2 links one-carbon metabolism to unfolded protein response in glioblastoma
Zhu, Z., Kiang, K. M. Y., Li, N., Liu, J., Zhang, P., Jin, L., He, X., Zhang, S., & Leung, G. (2022) · Cancer Letters · doi:10.1016/j.canlet.2022.215903 · Cited by 34 · see citing works
Tang, N., Chen, P., Zhao, C., Liu, P., Tan, L., Song, C., Qiu, X., Liao, Y., Liu, X., Luo, T., et al. (2023) · Journal of Virology · doi:10.1128/jvi.00016-23 · Cited by 31 · see citing works
Bazer, F. W., Seo, H., Johnson, G. A., & Wu, G. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-54462-1_1 · Cited by 30 · see citing works
The role of mitochondrial folate enzyme MTHFD1L in esophageal squamous cell carcinoma
Yang, Y., Yuan, Y., Hu, W., Shang, Q.-X., & Chen, L.-Q. (2017) · Scandinavian Journal of Gastroenterology · doi:10.1080/00365521.2017.1407440 · Cited by 30 · see citing works
Micro RNA ‐33a‐5p suppresses colorectal cancer cell growth by inhibiting MTHFD 2
Yan, Y., Zhang, D., Lei, T., Zhao, C., Han, J., Cui, J., & Wang, Y. (2019) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.13125 · Cited by 29 · see citing works
Metabolic determinants of germinal center B cell formation and responses
Wu, J., Zhou, J., Li, G. L., Sun, X., Xiang, C., Chen, H., & Jiang, P. (2024) · Nature Chemical Biology · doi:10.1038/s41589-024-01690-6 · Cited by 28 · see citing works
Hung, Y.-H., Huang, H.-L., Chen, W.-C., Yen, M., Cho, C.-Y., Weng, T., Wang, C., Chen, Y., Chen, L., & Lai, M.-D. (2016) · Oncology Reports · doi:10.3892/or.2016.5334 · Cited by 28 · see citing works
Gu, Y., Si, J., Xiao, X., Tian, Y., & Yang, S. (2017) · Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics · doi:10.3727/096504016x14829256525028 · Cited by 28 · see citing works
MTHFD2 in healthy and cancer cells: Canonical and non-canonical functions
Lorente, N. P., & Sdelci, S. (2024) · npj Metabolic Health and Disease · doi:10.1038/s44324-024-00005-6 · Cited by 27 · see citing works
Matheson, L. S., Petkau, G., Sáenz‐Narciso, B., D’Angeli, V., McHugh, J., Newman, R., Munford, H., West, J. A., Chakraborty, K., Roberts, J., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-24132-6 · Cited by 24 · see citing works
Cheng, D., Zhang, H., Yuan, J., Li, S.-J., Yang, Q., & Fan, C. (2017) · Oncotarget · doi:10.18632/oncotarget.15474 · Cited by 26 · see citing works
Zou, Z., Liu, J., Chang, C., Li, J., Luo, J., Jin, Y., Ma, Z., Wang, T., & Shao, J. (2019) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2019.4064 · Cited by 26 · see citing works
Metabolic Intermediates in Tumorigenesis and Progression
He, Y., Gao, M., Tang, H., Cao, Y., Liu, S., & Tao, Y. (2019) · International Journal of Biological Sciences · doi:10.7150/ijbs.33496 · Cited by 25 · see citing works
Min, D.-J., Vural, S., & Krushkal, J. (2019) · Cancer Genetics · doi:10.1016/j.cancergen.2019.05.005 · Cited by 23 · see citing works
Yang, Y., Ren, Z., Xu, F., Meng, Y., Zhang, Y., Ai, N., Long, Y., Fok, H. I., Deng, C., Zhao, X., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.11.047 · Cited by 23 · see citing works
Schubert, K. A., Karkossa, I., Schor, J., Engelmann, B., Steinheuer, L. M., Bruns, T., Rolle-Kampczyk, U. E., Jörg Hackermüller, A., & von Bergen�, M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.616967 · Cited by 20 · see citing works
Das, A., Madeshiya, A. K., Biswas, N., Ghosh, N., Gorain, M., Rawat, A. K., Mahajan, S. P., Khanna, S., Sen, C. K., & Roy, S. (2021) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2021.04.039 · Cited by 19 · see citing works
Scaletti, E. R., Westergren, R. G., Andersson, Y., Wiita, E., Henriksson, M., Homan, E. J., Jemth, A., Helleday, T., & Stenmark, P. (2022) · ChemMedChem · doi:10.1002/cmdc.202200274 · Cited by 19 · see citing works
Alhawarri, M. B. (2024) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-024-01474-8 · Cited by 19 · see citing works
Wu, S., Cai, W., Shi, Z., Ming, X., Yang, X., Zhou, Y., Chen, X., & Yang, M. (2022) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2022.05.007 · Cited by 18 · see citing works
Folate Metabolism in Hepatocellular Carcinoma. What Do We Know So Far?
Quevedo-Ocampo, J., Escobedo‐Calvario, A., Souza-Arroyo, V., Miranda-Labra, R. U., Bucio, L., Gutiérrez‐Ruíz, M. C., Chávez-Rodríguez, L., & Gómez-Quiroz, L. E. (2022) · Technology in Cancer Research & Treatment · doi:10.1177/15330338221144446 · Cited by 18 · see citing works
Folate pathways mediating the effects of ethanol in tumorigenesis
Sharma, J., & Krupenko, S. A. (2020) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2020.109091 · Cited by 18 · see citing works
Cui, L., Chen, H., & Zhao, X.-Y. (2020) · Diagnostics · doi:10.3390/diagnostics10090689 · Cited by 15 · see citing works
Nuclear localization of MTHFD2 is required for correct mitosis progression
Lorente, N. P., Gkanogiannis, A., Cozzuto, L., Zapater, A. G., Espinar, L., Ghose, R., Severino, J., García-López, L., Aydin, R. G., Martin, L., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-51847-z · Cited by 13 · see citing works
Shukla, K., Singh, N., Lewis, J. E., Tsang, A. W., Boothman, D. A., Kemp, M. L., & Furdui, C. M. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.536377 · Cited by 13 · see citing works
de Candia, P., & Matarese, G. (2022) · Immunity · doi:10.1016/j.immuni.2021.12.009 · Cited by 11 · see citing works
MTHFD1L knockdown diminished cells growth in papillary thyroid cancer
Yi, D., Yilihamu, Y., Jiang, C., Wang, R., Lu, X., Sang, J., & Su, L. (2022) · Tissue and Cell · doi:10.1016/j.tice.2022.101869 · Cited by 11 · see citing works
MTHFD2: A significant mitochondrial metabolic enzyme and a novel target for anticancer therapy
Liu, S., Wang, X., Zhao, L., Zhang, L., & Song, Y. (2025) · Drug Discovery Today · doi:10.1016/j.drudis.2025.104372 · Cited by 10 · see citing works
Jia, M., Fu, Z., Ye, C., Xu, W., Liu, J., Wu, C., & Yan, H. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02498-6 · Cited by 10 · see citing works
MTHFD2 suppresses glioblastoma progression via the inhibition of ERK1/2 phosphorylation
Huang, M., Xue, J., Chen, Z., Zhou, X. C., Chen, M., Sun, J., Xu, Z., Wang, S., Xu, H., Du, Z., et al. (2022) · Biochemistry and Cell Biology · doi:10.1139/bcb-2022-0291 · Cited by 8 · see citing works
Chan, C.-H., Wu, C.-Y., Dubey, N. K., Wei, H.-J., Lu, J.-H., Mao, S., Liang, J. N., Liang, Y.-H., Cheng, H.-C., & Deng, W. (2020) · Aging · doi:10.18632/aging.103471 · Cited by 8 · see citing works
Zhang, Y., Zhang, N., Liu, L., Wang, Y., Xing, J., & Li, X. (2021) · Frontiers in Veterinary Science · doi:10.3389/fvets.2021.686609 · Cited by 7 · see citing works
Yee, M., McDavid, A., Cohen, E. D., Huyck, H. L., Poole, C., Altman, B. J., Maniscalco, W. M., Deutsch, G. H., Pryhuber, G., & O’Reilly, M. A. (2022) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2021-0363oc · Cited by 7 · see citing works
Kundu, S., Rohokale, R., Lin, C., Chen, S., Biswas, S., & Guo, Z. (2024) · Journal of Lipid Research · doi:10.1016/j.jlr.2024.100570 · Cited by 7 · see citing works
Selectivity analysis of diaminopyrimidine-based inhibitors of MTHFD1, MTHFD2 and MTHFD2L
Jha, V., & Eriksson, L. A. (2024) · Scientific Reports · doi:10.1038/s41598-024-71879-1 · Cited by 7 · see citing works
Schmidt, A., Pfeiffer, M., & Sdelci, S. (2026) · npj Metabolic Health and Disease · doi:10.1038/s44324-025-00097-8 · Cited by 6 · see citing works
Trott, J. F., Schennink, A., Horigan, K. C., Lemay, D. G., Cohen, J. R., Famula, T. R., Dragon, J. A., & Hovey, R. C. (2021) · Endocrinology · doi:10.1210/endocr/bqab256 · Cited by 6 · see citing works
Tedeschi, P. M., Scotto, K. W., Kerrigan, J. E., & Bertino, J. R. (2016) · Oncotarget · doi:10.18632/oncotarget.7147 · Cited by 5 · see citing works
Abuelsamen, A., Alhawarri, M. B., Al-Thiabat, M. G., Makhadmeh, G. N., AlZoubi, T., Alrimawi, B. H., & Khaleel, M. A. (2025) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-025-01732-3 · Cited by 4 · see citing works
Binding Modes of Xanthine‐Derived Selective Allosteric Site Inhibitors of MTHFD2
Jha, V., & Eriksson, L. A. (2023) · ChemistryOpen · doi:10.1002/open.202300052 · Cited by 4 · see citing works
Whether MTHFD2 plays a new role: from anticancer targets to anti-inflammatory disease
Tang, H. R., & Hou, N. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1257107 · Cited by 4 · see citing works
Alshammari, S. O. (2024) · Processes · doi:10.3390/pr12061177 · Cited by 3 · see citing works
Lin, J., Weng, J., Lin, S., Lin, C., Huang, J., Zhang, C., Zhang, S., Dong, C., Ji, H., & Ke, X. (2021) · Japanese Journal of Clinical Oncology · doi:10.1093/jjco/hyab075 · Cited by 3 · see citing works
Nicolaidou, V., Papaneophytou, C. P., & Koufaris, C. (2020) · Molecular Biology Reports · doi:10.1007/s11033-020-05775-y · Cited by 3 · see citing works
Chen, D., Li, H., Zhang, H., Li, Q., Huang, Y., & Liu, H. (2020) · doi:10.21203/rs.3.rs-96109/v1 · Cited by 3 · see citing works
MTHFD2 marks pemetrexed resistance in pulmonary adenocarcinoma with EGFR wild type
Yao, S., Elakad, O., Yang, X., Altaf, A. R., Yu, W. T., Bohnenberger, H., & Peng, L. G. (2025) · Discover Oncology · doi:10.1007/s12672-025-02355-z · Cited by 2 · see citing works
MTHFD2 Expression Profile and Its Prognostic Importance in Invasive Breast Carcinoma
Arslan, R., & Ceylan, O. (2022) · International Journal Of Medical Science And Clinical Invention · doi:10.18535/ijmsci/v9i03.08 · Cited by 2 · see citing works
Nuclear MTHFD2 secures mitosis progression by preserving centromere integrityPreprint
Lorente, N. P., Gkanogiannis, A., Cozzuto, L., Zapater, A. G., Espinar, L., García-López, L., Aydin, R. G., Darai, E., Severino, J., Batlle‐Morera, L., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.06.01.543193 · Cited by 2 · see citing works
Morgan, A. E., Salcedo-Sora, J. E., & Auley, M. T. M. (2023) · Biosystems · doi:10.1016/j.biosystems.2023.105088 · Cited by 1 · see citing works
Marttila, P., Bonagas, N., Chalkiadaki, C., Stigsdotter, H., Schelzig, K., Shen, J., Farhat, C. M., Hondema, A., Albers, J. J., Wiita, E., et al. (2024) · Molecular Oncology · doi:10.1002/1878-0261.13645 · Cited by 1 · see citing works
MTHFD2: A Retrospective and a Glance into the Future
Koufaris, C., & Nicolaidou, V. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262211025 · Cited by 1 · see citing works
Parreiras, S., & Serpa, J. (2026) · Advances in experimental medicine and biology · doi:10.1007/978-3-032-12166-0_15 · Cited by 1 · see citing works
Epigenetics and One-Carbon Metabolism in Cancer: Mechanisms and Therapeutic Implications
Serpa, J., & Costa, J. R. (2026) · Advances in experimental medicine and biology · doi:10.1007/978-3-032-12166-0_9 · Cited by 1 · see citing works
Eldredge, L. C. (2022) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2022-0012ed · Cited by 1 · see citing works
Folate trapping is lethal to cancer cells
Rather, G. M. (2023) · Chemical Biology & Drug Design · doi:10.1111/cbdd.14329 · Cited by 1 · see citing works
(2024) · Frontiers research topics · doi:10.3389/978-2-8325-4643-7 · Cited by 1 · see citing works
A formative time in our understanding of formate
Miller, J. W. (2019) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqz216 · Cited by 1 · see citing works
Wei, C., Huang, L., Deng, L., Lin, H., Pan, W., & Pang, L. (2021) · Research Square · doi:10.21203/rs.3.rs-318398/v1 · Cited by 1 · see citing works
Matheson, L. S., Petkau, G., Sáenz‐Narciso, B., D’Angeli, V., McHugh, J., Newman, R., Munford, H., West, J. A., Chakraborty, K., Roberts, J., et al. (2022) · Research Square · doi:10.21203/rs.3.rs-1862066/v1 · Cited by 1 · see citing works
Sun, B., He, Z., Liu, G., Fu, X., Chen, Z., & Li, G. (2021) · Pteridines · doi:10.1515/pteridines-2020-0033
- Authors
- Gustafsson Sheppard, N., Jarl, L., Mahadessian, D., Strittmatter, L., Schmidt, A., Madhusudan, N., Tegnér, J., Lundberg, E. K., Asplund, A., Jain, M., & Nilsson, R.
- Affiliations
- Karolinska Institutet (SE)
- Science for Life Laboratory (SE)
- Massachusetts General Hospital (US)
- Uppsala University (SE)
- University of California San Diego (US)
- Corresponding author
- Nilsson, Roland
- Venue
- Scientific Reports
- Published
- 2015-10-13
- Volume
- 5
- Issue
- 1
- Pages
- 15029-15029
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4602236
- OpenAlex
- W1936240797
- Cited by
- 115
- References
- 32
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 10 · 2023: 12 · 2022: 17 · 2021: 17 · 2020: 17 · 2019: 9 · 2018: 6 · 2017: 5 · 2016: 7
- FWCI
- 5.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Uppsala University Publications (Uppsala University) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Jeanssons Stiftelser
- Cancerfonden
- Svenska Sällskapet för Medicinsk Forskning
- Karolinska Institutet
- Stockholms Läns Landsting
- Topics
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- MTHFD2, folate metabolism, cell proliferation, nuclear localization, amino acid metabolism, cancer cells, serum stimulation, dehydrogenase activity
- MeSH terms
- Animals, Cell Nucleus, Folic Acid, HeLa Cells, Humans, Methylenetetrahydrofolate Dehydrogenase (NADP), Mitochondria, Neoplasms, Experimental, Nuclear Proteins, Species Specificity, Cell Line, Tumor, Cell Proliferation, Amino-Acid N-Acetyltransferase, Mice, Rats
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