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Sökning: WFRF:(Cookson J) > (2020-2024) > Formate overflow dr...

Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells

Green, Alanna C. (författare)
Karolinska Institutet
Marttila, Petra (författare)
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
Kiweler, Nicole (författare)
Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
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Chalkiadaki, Christina (författare)
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
Wiita, Elisée (författare)
Karolinska Institutet
Cookson, Victoria (författare)
Weston Park Cancer Centre and Mellanby Centre for Musculoskeletal Research, Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, United Kingdom
Lesur, Antoine (författare)
Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
Eiden, Kim (författare)
Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
Bernardin, François (författare)
Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
Vallin, Karl (författare)
RISE,Kemiska processer och läkemedel,Karolinska Institute, Sweden
Borhade, Sanjay (författare)
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden; RedGlead Discover, Lund, Sweden
Long, Maeve (författare)
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
Ghahe, Elahe Kamali (författare)
Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
Jiménez-Alonso, Julio J. (författare)
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden; Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain
Jemth, Ann-Sofie (författare)
Karolinska Institutet
Loseva, Olga (författare)
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
Mortusewicz, Oliver (författare)
Karolinska Institutet
Meyers, Marianne (författare)
Karolinska Institutet
Viry, Elodie (författare)
Tumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
Johansson, Annika I. (författare)
Umeå universitet,Institutionen för fysiologisk botanik
Hodek, Ondřej (författare)
Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för skoglig genetik och växtfysiologi,Department of Forest Genetics and Plant Physiology
Homan, Evert (författare)
Karolinska Institutet
Bonagas, Nadilly (författare)
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
Ramos, Louise (författare)
Weston Park Cancer Centre and Mellanby Centre for Musculoskeletal Research, Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, United Kingdom
Sandberg, Lars (författare)
Stockholms universitet,Institutionen för organisk kemi,Science for Life Laboratory (SciLifeLab)
Frödin, Morten (författare)
Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
Moussay, Etienne (författare)
Tumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
Slipicevic, Ana (författare)
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden; One-carbon Therapeutics AB, Stockholm, Sweden
Letellier, Elisabeth (författare)
Faculty of Science, Technology and Medicine, Department of Life Sciences and Medicine, Molecular Disease Mechanisms Group, University of Luxembourg, Esch-sur-Alzette, Luxembourg
Paggetti, Jérôme (författare)
Tumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
Sørensen, Claus Storgaard (författare)
Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
Helleday, Thomas (författare)
Karolinska Institutet
Henriksson, Martin (författare)
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
Meiser, Johannes (författare)
Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
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 (creator_code:org_t)
 
Springer Nature, 2023
2023
Engelska.
Ingår i: Nature Metabolism. - : Springer Nature. - 2522-5812. ; 5:4, s. 642-659
Relaterad länk:
https://doi.org/10.1...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • 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.

Ämnesord

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)

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