Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells. / Green, Alanna C; Marttila, Petra; Kiweler, Nicole; Chalkiadaki, Christina; Wiita, Elisée; Cookson, Victoria; Lesur, Antoine; Eiden, Kim; Bernardin, François; Vallin, Karl S A; Borhade, Sanjay; Long, Maeve; Ghahe, Elahe Kamali; Jiménez-Alonso, Julio J; Jemth, Ann-Sofie; Loseva, Olga; Mortusewicz, Oliver; Meyers, Marianne; Viry, Elodie; Johansson, Annika I; Hodek, Ondřej; Homan, Evert; Bonagas, Nadilly; Ramos, Louise; Sandberg, Lars; Frödin, Morten; Moussay, Etienne; Slipicevic, Ana; Letellier, Elisabeth; Paggetti, Jérôme; Sørensen, Claus Storgaard; Helleday, Thomas; Henriksson, Martin; Meiser, Johannes.

In: Nature Metabolism, Vol. 5, 2023, p. 642-659.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Green, AC, Marttila, P, Kiweler, N, Chalkiadaki, C, Wiita, E, Cookson, V, Lesur, A, Eiden, K, Bernardin, F, Vallin, KSA, Borhade, S, Long, M, Ghahe, EK, Jiménez-Alonso, JJ, Jemth, A-S, Loseva, O, Mortusewicz, O, Meyers, M, Viry, E, Johansson, AI, Hodek, O, Homan, E, Bonagas, N, Ramos, L, Sandberg, L, Frödin, M, Moussay, E, Slipicevic, A, Letellier, E, Paggetti, J, Sørensen, CS, Helleday, T, Henriksson, M & Meiser, J 2023, 'Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells', Nature Metabolism, vol. 5, pp. 642-659. https://doi.org/10.1038/s42255-023-00771-5

APA

Green, A. C., Marttila, P., Kiweler, N., Chalkiadaki, C., Wiita, E., Cookson, V., Lesur, A., Eiden, K., Bernardin, F., Vallin, K. S. A., Borhade, S., Long, M., Ghahe, E. K., Jiménez-Alonso, J. J., Jemth, A-S., Loseva, O., Mortusewicz, O., Meyers, M., Viry, E., ... Meiser, J. (2023). Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells. Nature Metabolism, 5, 642-659. https://doi.org/10.1038/s42255-023-00771-5

Vancouver

Green AC, Marttila P, Kiweler N, Chalkiadaki C, Wiita E, Cookson V et al. Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells. Nature Metabolism. 2023;5:642-659. https://doi.org/10.1038/s42255-023-00771-5

Author

Green, Alanna C ; Marttila, Petra ; Kiweler, Nicole ; Chalkiadaki, Christina ; Wiita, Elisée ; Cookson, Victoria ; Lesur, Antoine ; Eiden, Kim ; Bernardin, François ; Vallin, Karl S A ; Borhade, Sanjay ; Long, Maeve ; Ghahe, Elahe Kamali ; Jiménez-Alonso, Julio J ; Jemth, Ann-Sofie ; Loseva, Olga ; Mortusewicz, Oliver ; Meyers, Marianne ; Viry, Elodie ; Johansson, Annika I ; Hodek, Ondřej ; Homan, Evert ; Bonagas, Nadilly ; Ramos, Louise ; Sandberg, Lars ; Frödin, Morten ; Moussay, Etienne ; Slipicevic, Ana ; Letellier, Elisabeth ; Paggetti, Jérôme ; Sørensen, Claus Storgaard ; Helleday, Thomas ; Henriksson, Martin ; Meiser, Johannes. / Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells. In: Nature Metabolism. 2023 ; Vol. 5. pp. 642-659.

Bibtex

@article{ddac976c06a748e6b7d23ec7da3f5a36,
title = "Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells",
abstract = "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.",
author = "Green, {Alanna C} and Petra Marttila and Nicole Kiweler and Christina Chalkiadaki and Elis{\'e}e Wiita and Victoria Cookson and Antoine Lesur and Kim Eiden and Fran{\c c}ois Bernardin and Vallin, {Karl S A} and Sanjay Borhade and Maeve Long and Ghahe, {Elahe Kamali} and Jim{\'e}nez-Alonso, {Julio J} and Ann-Sofie Jemth and Olga Loseva and Oliver Mortusewicz and Marianne Meyers and Elodie Viry and Johansson, {Annika I} and Ond{\v r}ej Hodek and Evert Homan and Nadilly Bonagas and Louise Ramos and Lars Sandberg and Morten Fr{\"o}din and Etienne Moussay and Ana Slipicevic and Elisabeth Letellier and J{\'e}r{\^o}me Paggetti and S{\o}rensen, {Claus Storgaard} and Thomas Helleday and Martin Henriksson and Johannes Meiser",
note = "{\textcopyright} 2023. The Author(s).",
year = "2023",
doi = "10.1038/s42255-023-00771-5",
language = "English",
volume = "5",
pages = "642--659",
journal = "Nature Metabolism",
issn = "2522-5812",
publisher = "Springer",

}

RIS

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 - © 2023. The Author(s).

PY - 2023

Y1 - 2023

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.

U2 - 10.1038/s42255-023-00771-5

DO - 10.1038/s42255-023-00771-5

M3 - Journal article

C2 - 37012496

VL - 5

SP - 642

EP - 659

JO - Nature Metabolism

JF - Nature Metabolism

SN - 2522-5812

ER -

ID: 342921429