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Formate overflow dr...
Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells
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- Green, Alanna C. (author)
- Karolinska Institutet
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- Marttila, Petra (author)
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
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- Kiweler, Nicole (author)
- Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
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- Chalkiadaki, Christina (author)
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
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- Wiita, Elisée (author)
- Karolinska Institutet
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- Cookson, Victoria (author)
- Weston Park Cancer Centre and Mellanby Centre for Musculoskeletal Research, Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, United Kingdom
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- Lesur, Antoine (author)
- Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
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- Eiden, Kim (author)
- Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
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- Bernardin, François (author)
- Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
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- Vallin, Karl (author)
- RISE,Kemiska processer och läkemedel,Karolinska Institute, Sweden
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- Borhade, Sanjay (author)
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden; RedGlead Discover, Lund, Sweden
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- Long, Maeve (author)
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
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- Ghahe, Elahe Kamali (author)
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
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- Jiménez-Alonso, Julio J. (author)
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden; Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain
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- Jemth, Ann-Sofie (author)
- Karolinska Institutet
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- Loseva, Olga (author)
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
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- Mortusewicz, Oliver (author)
- Karolinska Institutet
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- Meyers, Marianne (author)
- Karolinska Institutet
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- Viry, Elodie (author)
- Tumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
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- Johansson, Annika I. (author)
- Umeå universitet,Institutionen för fysiologisk botanik
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- Hodek, Ondřej (author)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för skoglig genetik och växtfysiologi,Department of Forest Genetics and Plant Physiology
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- Homan, Evert (author)
- Karolinska Institutet
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- Bonagas, Nadilly (author)
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
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- Ramos, Louise (author)
- Weston Park Cancer Centre and Mellanby Centre for Musculoskeletal Research, Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, United Kingdom
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- Sandberg, Lars (author)
- Stockholms universitet,Institutionen för organisk kemi,Science for Life Laboratory (SciLifeLab)
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- Frödin, Morten (author)
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
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- Moussay, Etienne (author)
- Tumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
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- Slipicevic, Ana (author)
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden; One-carbon Therapeutics AB, Stockholm, Sweden
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- Letellier, Elisabeth (author)
- Faculty of Science, Technology and Medicine, Department of Life Sciences and Medicine, Molecular Disease Mechanisms Group, University of Luxembourg, Esch-sur-Alzette, Luxembourg
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- Paggetti, Jérôme (author)
- Tumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
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- Sørensen, Claus Storgaard (author)
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
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- Helleday, Thomas (author)
- Karolinska Institutet
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- Henriksson, Martin (author)
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
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- Meiser, Johannes (author)
- Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
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(creator_code:org_t)
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- Springer Nature, 2023
- 2023
- English.
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In: Nature Metabolism. - : Springer Nature. - 2522-5812. ; 5:4, s. 642-659
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Abstract
Subject headings
Close
- 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
- NATURVETENSKAP -- Biologi -- Cellbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Cell Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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Green, Alanna C.
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Marttila, Petra
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Kiweler, Nicole
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Chalkiadaki, Chr ...
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Wiita, Elisée
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Cookson, Victori ...
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show more...
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Lesur, Antoine
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Eiden, Kim
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Bernardin, Franç ...
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Vallin, Karl
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Borhade, Sanjay
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Long, Maeve
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Ghahe, Elahe Kam ...
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Jiménez-Alonso, ...
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Jemth, Ann-Sofie
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Loseva, Olga
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Mortusewicz, Oli ...
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Meyers, Marianne
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Viry, Elodie
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Johansson, Annik ...
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Hodek, Ondřej
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Homan, Evert
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Bonagas, Nadilly
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Ramos, Louise
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Sandberg, Lars
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Frödin, Morten
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Moussay, Etienne
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Slipicevic, Ana
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Letellier, Elisa ...
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Paggetti, Jérôme
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Sørensen, Claus ...
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Helleday, Thomas
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Henriksson, Mart ...
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Meiser, Johannes
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- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Cell Biology
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
- Articles in the publication
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Nature Metabolis ...
- By the university
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Umeå University
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Stockholm University
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RISE
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Karolinska Institutet
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Swedish University of Agricultural Sciences