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FältnamnIndikatorerMetadata
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001oai:DiVA.org:umu-206656
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0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-2066562 URI
0247 a https://doi.org/10.1038/s42255-023-00771-52 DOI
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-2180522 URI
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041 a engb eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Green, Alanna C.u Karolinska Institutet4 aut
2451 0a Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells
264 1b Springer Nature,c 2023
338 a electronic2 rdacarrier
500 a 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.
520 a 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.
650 7a NATURVETENSKAPx Biologix Cellbiologi0 (SwePub)106042 hsv//swe
650 7a NATURAL SCIENCESx Biological Sciencesx Cell Biology0 (SwePub)106042 hsv//eng
650 7a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Cancer och onkologi0 (SwePub)302032 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Cancer and Oncology0 (SwePub)302032 hsv//eng
650 7a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Cell- och molekylärbiologi0 (SwePub)301082 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Cell and Molecular Biology0 (SwePub)301082 hsv//eng
7001 a Marttila, Petrau Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden4 aut
7001 a Kiweler, Nicoleu Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg4 aut
7001 a Chalkiadaki, Christinau Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden4 aut
7001 a Wiita, Eliséeu Karolinska Institutet4 aut
7001 a Cookson, Victoriau Weston Park Cancer Centre and Mellanby Centre for Musculoskeletal Research, Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, United Kingdom4 aut
7001 a Lesur, Antoineu Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg4 aut
7001 a Eiden, Kimu Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg4 aut
7001 a Bernardin, Françoisu Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg4 aut
7001 a Vallin, Karlu RISE,Kemiska processer och läkemedel,Karolinska Institute, Sweden4 aut0 (Swepub:ri)karlva@ri.se
7001 a Borhade, Sanjayu Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden; RedGlead Discover, Lund, Sweden4 aut
7001 a Long, Maeveu Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden4 aut
7001 a Ghahe, Elahe Kamaliu Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark4 aut
7001 a Jiménez-Alonso, Julio J.u Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden; Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain4 aut
7001 a Jemth, Ann-Sofieu Karolinska Institutet4 aut
7001 a Loseva, Olgau Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden4 aut
7001 a Mortusewicz, Oliveru Karolinska Institutet4 aut
7001 a Meyers, Marianneu Karolinska Institutet4 aut
7001 a Viry, Elodieu Tumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg4 aut
7001 a Johansson, Annika I.u Umeå universitet,Institutionen för fysiologisk botanik4 aut0 (Swepub:umu)joan5601
7001 a Hodek, Ondřeju Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för skoglig genetik och växtfysiologi,Department of Forest Genetics and Plant Physiology4 aut
7001 a Homan, Evertu Karolinska Institutet4 aut
7001 a Bonagas, Nadillyu Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden4 aut
7001 a Ramos, Louiseu Weston Park Cancer Centre and Mellanby Centre for Musculoskeletal Research, Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, United Kingdom4 aut
7001 a Sandberg, Larsu Stockholms universitet,Institutionen för organisk kemi,Science for Life Laboratory (SciLifeLab)4 aut0 (Swepub:su)lasa3159
7001 a Frödin, Mortenu Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark4 aut
7001 a Moussay, Etienneu Tumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg4 aut
7001 a Slipicevic, Anau Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden; One-carbon Therapeutics AB, Stockholm, Sweden4 aut
7001 a Letellier, Elisabethu Faculty of Science, Technology and Medicine, Department of Life Sciences and Medicine, Molecular Disease Mechanisms Group, University of Luxembourg, Esch-sur-Alzette, Luxembourg4 aut
7001 a Paggetti, Jérômeu Tumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg4 aut
7001 a Sørensen, Claus Storgaardu Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark4 aut
7001 a Helleday, Thomasu Karolinska Institutet4 aut
7001 a Henriksson, Martinu Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden4 aut
7001 a Meiser, Johannesu Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg4 aut
7102 a Karolinska Institutetb Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden4 org
7102 a Sveriges lantbruksuniversitet
7730 t Nature Metabolismd : Springer Natureg 5:4, s. 642-659q 5:4<642-659x 2522-5812
8564 u https://doi.org/10.1038/s42255-023-00771-5y Fulltext
8564 u https://umu.diva-portal.org/smash/get/diva2:1750663/FULLTEXT02.pdfx primaryx Raw objecty fulltext:print
8564 u https://pub.epsilon.slu.se/id/eprint/31053/contentsx primaryx Raw objectx freey FULLTEXT
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-206656
8564 8u https://doi.org/10.1038/s42255-023-00771-5
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-218052
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:ri:diva-64338
8564 8u http://kipublications.ki.se/Default.aspx?queryparsed=id:152588374
8564 8u https://res.slu.se/id/publ/122284

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