TY - JOUR
T1 - Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells
AU - Green, Alanna C.
AU - Marttila, Petra
AU - Kiweler, Nicole
AU - Chalkiadaki, Christina
AU - Wiita, Elisée
AU - Cookson, Victoria
AU - Lesur, Antoine
AU - Eiden, Kim
AU - Bernardin, François
AU - Vallin, Karl S.A.
AU - Borhade, Sanjay
AU - Long, Maeve
AU - Ghahe, Elahe Kamali
AU - Jiménez-Alonso, Julio J.
AU - Jemth, Ann Sofie
AU - Loseva, Olga
AU - Mortusewicz, Oliver
AU - Meyers, Marianne
AU - Viry, Elodie
AU - Johansson, Annika I.
AU - Hodek, Ondřej
AU - Homan, Evert
AU - Bonagas, Nadilly
AU - Ramos, Louise
AU - Sandberg, Lars
AU - Frödin, Morten
AU - Moussay, Etienne
AU - Slipicevic, Ana
AU - Letellier, Elisabeth
AU - Paggetti, Jérôme
AU - Sørensen, Claus Storgaard
AU - Helleday, Thomas
AU - Henriksson, Martin
AU - Meiser, Johannes
N1 - Funding Information:
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.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/4/20
Y1 - 2023/4/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85151482683&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/37012496
U2 - 10.1038/s42255-023-00771-5
DO - 10.1038/s42255-023-00771-5
M3 - Article
C2 - 37012496
SN - 2522-5812
VL - 5
SP - 642
EP - 659
JO - Nature Metabolism
JF - Nature Metabolism
IS - 4
ER -