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Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells
Weston Park Cancer Centre and Mellanby Centre for Musculoskeletal Research, Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, United Kingdom.
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
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2023 (English)In: Nature Metabolism, E-ISSN 2522-5812, Vol. 5, no 4, p. 642-659Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Springer Nature, 2023. Vol. 5, no 4, p. 642-659
National Category
Cell Biology Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-206656DOI: 10.1038/s42255-023-00771-5ISI: 000962791100003PubMedID: 37012496Scopus ID: 2-s2.0-85151482683OAI: oai:DiVA.org:umu-206656DiVA, id: diva2:1750663
Funder
Novo Nordisk Foundation, 17OC0029972Swedish Cancer Society, 2018/600Swedish Cancer Society, 2021/1490Swedish Childhood Cancer Foundation, 2018-0095Swedish Childhood Cancer Foundation, 2021-0030Swedish Research Council, 2015-00162Swedish Research Council, 2017-06095Vinnova, 2018-00257Vinnova, 2021-04817Torsten Söderbergs stiftelseAvailable from: 2023-04-14 Created: 2023-04-14 Last updated: 2023-09-05Bibliographically approved

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Johansson, Annika I.

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