Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells
Number of Authors: 342023 (English)In: Nature Metabolism, E-ISSN 2522-5812, Vol. 5, no 4, p. 642-Article 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. © 2023, The Author(s).
Place, publisher, year, edition, pages
Nature Research , 2023. Vol. 5, no 4, p. 642-
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:ri:diva-64338DOI: 10.1038/s42255-023-00771-5Scopus ID: 2-s2.0-85151482683OAI: oai:DiVA.org:ri-64338DiVA, id: diva2:1752305
Note
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.
2023-04-212023-04-212024-05-23Bibliographically approved