[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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Green, Alanna C ; Weston Park Cancer Centre and Mellanby Centre for Musculoskeletal Research, Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, UK
Marttila, Petra ; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
Kiweler, Nicole ; Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
Chalkiadaki, Christina; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
Wiita, Elisée; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
Cookson, Victoria; Weston Park Cancer Centre and Mellanby Centre for Musculoskeletal Research, Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, UK
Lesur, Antoine; Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
Eiden, Kim; Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
Bernardin, François ; Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
Vallin, Karl S A; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden ; RISE Research Institutes of Sweden, Södertälje, Sweden
Borhade, Sanjay; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden ; RedGlead Discover, Lund, Sweden
Long, Maeve; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
Ghahe, Elahe Kamali; Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
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
Jemth, Ann-Sofie ; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
Loseva, Olga; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
Mortusewicz, Oliver ; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
MEYERS, Marianne ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
VIRY, Elodie ; Tumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
Johansson, Annika I ; Swedish Metabolomics Centre, Department of Plant Physiology, Umeå University, Umeå, Sweden
Hodek, Ondřej ; Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå, Sweden
Homan, Evert; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
Bonagas, Nadilly ; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
Ramos, Louise ; Weston Park Cancer Centre and Mellanby Centre for Musculoskeletal Research, Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, UK
Sandberg, Lars; Drug Discovery and Development Platform, Science for Life Laboratory, Department of Organic Chemistry, Stockholm University, Solna, Sweden
Frödin, Morten; Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
MOUSSAY, Etienne ; Tumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
Slipicevic, Ana; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden ; One-carbon Therapeutics AB, Stockholm, Sweden
LETELLIER, Elisabeth ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
PAGGETTI, Jerome ; Tumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
Sørensen, Claus Storgaard; Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
Helleday, Thomas ; Weston Park Cancer Centre and Mellanby Centre for Musculoskeletal Research, Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, UK. thomas.helleday@scilifelab.se ; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden. thomas.helleday@scilifelab.se
Henriksson, Martin ; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden. martin.henriksson@scilifelab.se
MEISER, Johannes ; Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg. Johannes.Meiser@lih.lu
Weston Park Cancer Centre and the University of Sheffield Helleday Foundation Deutsche Forschungsgemeinschaft Fonds National de la Recherche Luxembourg Ministerio de Universidades of the Spanish Government Karolinska Institute’s KID funding for doctoral students One-Carbon Therapeutics AB Novo Nordisk Fonden Cancerfonden Barncancerfonden Vetenskapsrådet VINNOVA Weston Park Cancer Centre and the University of Sheffield Torsten and Ragnar Söderberg Foundation
Funding text :
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.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.
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