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  • Green, Alanna C.Karolinska Institutet (author)

Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells

  • Article/chapterEnglish2023

Publisher, publication year, extent ...

  • Springer Nature,2023
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:umu-206656
  • https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-206656URI
  • https://doi.org/10.1038/s42255-023-00771-5DOI
  • https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-218052URI
  • https://urn.kb.se/resolve?urn=urn:nbn:se:ri:diva-64338URI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:152588374URI
  • https://res.slu.se/id/publ/122284URI

Supplementary language notes

  • Language:English
  • Summary in:English

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Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Funding details: A18/BM/11809970; Funding details: C21/BM/15718879; Funding details: PRIDE19/14254520; Funding details: 7.4509.20, 7.4572.22; Funding details: FPU17/02185; Funding details: 2018-0095, 2021-0030; Funding details: Torsten Söderbergs Stiftelse, TSS; Funding details: Fondation Cancer, C20/BM/14582635, C20/BM/14592342; Funding details: University of Sheffield; Funding details: Deutsche Forschungsgemeinschaft, DFG, KI 2508/1-1; Funding details: VINNOVA, 2018-00257, 2021-04817; Funding details: Fonds National de la Recherche Luxembourg, FNR; Funding details: Cancerfonden, 2018/600, 2021/1490; Funding details: Karolinska Institutet, KI; Funding details: Vetenskapsrådet, VR, 2015-00162, 2017-06095; Funding details: Novo Nordisk Fonden, NNF, 17OC0029972; Funding text 1: We thank the members of the Helleday laboratory for fruitful discussions. We also thank M. Benzarti from the Cancer Metabolism Group at the Luxembourg Institute of Health and F. Rodriguez from the Molecular Disease Mechanisms Group at University of Luxembourg for their technical assistance and C. Jäger from the LCSB Metabolomics Platform at University of Luxembourg for providing technical and analytical support. This project is supported by the Weston Park Cancer Centre and the University of Sheffield (A.C.G. and T.H.), a DFG fellowship (no. KI 2508/1-1, N.K.), the Mobility programme for the FPU predoctoral fellowship from Ministerio de Universidades of the Spanish Government (grant no. FPU17/02185, J.J.J.-A.), the Helleday Foundation (P.M., C.C., S.B. and M.L.), Karolinska Institute’s KID funding for doctoral students (N.B.), the Novo Nordisk Foundation (grant no. 17OC0029972, T.H.), the Swedish Cancer Society (grant nos. 2018/600, 2021/1490, T.H.), the Swedish Children’s Cancer Foundation (grant nos. 2018-0095, 2021-0030, T.H.), the Swedish Research Council (grant nos. 2015-00162, 2017-06095, T.H.), Vinnova (grant nos. 2018-00257, 2021-04817, T.H.), Torsten and Ragnar Söderberg Foundation (T.H.), the Luxembourg National Research Fund (FNR) and Fondation Cancer (grant nos. C20/BM/14582635, E.M. and C20/BM/14592342, J.P.), the FNRS-Télévie (grant nos. 7.4509.20 and 7.4572.22, E.V.), the FNR-ATTRACT programme (A18/BM/11809970, J.M.), a FNR-CORE grant (no. C21/BM/15718879, J.M.) and the FNR-PRIDE i2Tron (grant no. PRIDE19/14254520, K.E.) programme.
  • Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase–cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a ‘folate trap’. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Marttila, PetraScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden (author)
  • Kiweler, NicoleCancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg (author)
  • Chalkiadaki, ChristinaScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden (author)
  • Wiita, EliséeKarolinska Institutet (author)
  • Cookson, VictoriaWeston Park Cancer Centre and Mellanby Centre for Musculoskeletal Research, Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, United Kingdom (author)
  • Lesur, AntoineCancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg (author)
  • Eiden, KimCancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg (author)
  • Bernardin, FrançoisCancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg (author)
  • Vallin, KarlRISE,Kemiska processer och läkemedel,Karolinska Institute, Sweden(Swepub:ri)karlva@ri.se (author)
  • Borhade, SanjayScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden; RedGlead Discover, Lund, Sweden (author)
  • Long, MaeveScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden (author)
  • Ghahe, Elahe KamaliBiotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark (author)
  • Jiménez-Alonso, Julio J.Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden; Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain (author)
  • Jemth, Ann-SofieKarolinska Institutet (author)
  • Loseva, OlgaScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden (author)
  • Mortusewicz, OliverKarolinska Institutet (author)
  • Meyers, MarianneKarolinska Institutet (author)
  • Viry, ElodieTumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg (author)
  • Johansson, Annika I.Umeå universitet,Institutionen för fysiologisk botanik(Swepub:umu)joan5601 (author)
  • Hodek, OndřejSwedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för skoglig genetik och växtfysiologi,Department of Forest Genetics and Plant Physiology (author)
  • Homan, EvertKarolinska Institutet (author)
  • Bonagas, NadillyScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden (author)
  • Ramos, LouiseWeston Park Cancer Centre and Mellanby Centre for Musculoskeletal Research, Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, United Kingdom (author)
  • Sandberg, LarsStockholms universitet,Institutionen för organisk kemi,Science for Life Laboratory (SciLifeLab)(Swepub:su)lasa3159 (author)
  • Frödin, MortenBiotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark (author)
  • Moussay, EtienneTumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg (author)
  • Slipicevic, AnaScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden; One-carbon Therapeutics AB, Stockholm, Sweden (author)
  • Letellier, ElisabethFaculty of Science, Technology and Medicine, Department of Life Sciences and Medicine, Molecular Disease Mechanisms Group, University of Luxembourg, Esch-sur-Alzette, Luxembourg (author)
  • Paggetti, JérômeTumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg (author)
  • Sørensen, Claus StorgaardBiotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark (author)
  • Helleday, ThomasKarolinska Institutet (author)
  • Henriksson, MartinScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden (author)
  • Meiser, JohannesCancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg (author)
  • Karolinska InstitutetScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden (creator_code:org_t)
  • Sveriges lantbruksuniversitet

Related titles

  • In:Nature Metabolism: Springer Nature5:4, s. 642-6592522-5812

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