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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Abstract
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 |
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Status: | Published |
Refereed: | Yes |
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: | 2211-1247 |
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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