SHMT2-mediated mitochondrial serine metabolism drives 5-FU resistance by fueling nucleotide biosynthesis

Pranzini, E. et al. (2022) SHMT2-mediated mitochondrial serine metabolism drives 5-FU resistance by fueling nucleotide biosynthesis. Cell Reports, 40(7), 111233. (doi: 10.1016/j.celrep.2022.111233) (PMID:35977477)

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5-Fluorouracil (5-FU) is a key component of chemotherapy for colorectal cancer (CRC). 5-FU efficacy is established by intracellular levels of folate cofactors and DNA damage repair strategies. However, drug resistance still represents a major challenge. Here, we report that alterations in serine metabolism affect 5-FU sensitivity in in vitro and in vivo CRC models. In particular, 5-FU-resistant CRC cells display a strong serine dependency achieved either by upregulating endogenous serine synthesis or increasing exogenous serine uptake. Importantly, regardless of the serine feeder strategy, serine hydroxymethyltransferase-2 (SHMT2)-driven compartmentalization of one-carbon metabolism inside the mitochondria represents a specific adaptation of resistant cells to support purine biosynthesis and potentiate DNA damage response. Interfering with serine availability or affecting its mitochondrial metabolism revert 5-FU resistance. These data disclose a relevant mechanism of mitochondrial serine use supporting 5-FU resistance in CRC and provide perspectives for therapeutic approaches.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Zhang, Mr Tong and Huerta Uribe, Mr Alejandro and Maddocks, Professor Oliver
Authors: Pranzini, E., Pardella, E., Muccillo, L., Leo, A., Nesi, I., Santi, A., Parri, M., Zhang, T., Huerta Uribe, A., Lottini, T., Sabatino, L., Caselli, A., Arcangeli, A., Raugei, G., Colantuoni, V., Cirri, P., Chiarugi, P., Maddocks, O. D. K., Paoli, P., and Taddei, M. L.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cell Reports
Publisher:Elsevier (Cell Press)
ISSN (Online):2211-1247
Published Online:16 August 2022
Copyright Holders:Copyright © 2022 The Author(s)
First Published:First published in Cell Reports 40(7): 111233
Publisher Policy:Reproduced under a Creative Commons License

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