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

SHMT2-mediated mitochondrial serine metabolism drives 5-FU resistance by fueling nucleotide biosynthesis / Erica Pranzini, Elisa Pardella, Livio Muccillo, Angela Leo, Ilaria Nesi, Alice Santi, Matteo Parri, Tong Zhang, Alejandro Huerta Uribe, Tiziano Lottini, Lina Sabatino, Anna Caselli, Annarosa Arcangeli, Giovanni Raugei, Vittorio Colantuoni, Paolo Cirri, Paola Chiarugi, Oliver D.K. Maddocks, Paolo Paoli, Maria Letizia Taddei. - In: CELL REPORTS. - ISSN 2211-1247. - ELETTRONICO. - Volume 40:(2022), pp. 1-28. [10.1016/j.celrep.2022.111233]

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

Erica Pranzini
;
Elisa Pardella;Angela Leo;Alice Santi;Matteo Parri;Tiziano Lottini;Anna Caselli;Annarosa Arcangeli;Giovanni Raugei;Paolo Cirri;Paola Chiarugi;Paolo Paoli
;
Maria Letizia Taddei
2022

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
Volume 40
1
28
Erica Pranzini, Elisa Pardella, Livio Muccillo, Angela Leo, Ilaria Nesi, Alice Santi, Matteo Parri, Tong Zhang, Alejandro Huerta Uribe, Tiziano Lottini, Lina Sabatino, Anna Caselli, Annarosa Arcangeli, Giovanni Raugei, Vittorio Colantuoni, Paolo Cirri, Paola Chiarugi, Oliver D.K. Maddocks, Paolo Paoli, Maria Letizia Taddei
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2158/1279679
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