丝氨酸羟甲基转移酶
丝氨酸
生物
线粒体
生物合成
生物化学
新陈代谢
磷酸化
基因
作者
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 De Paoli,Maria Letizia Taddei
出处
期刊:Cell Reports
[Elsevier]
日期:2022-08-01
卷期号:40 (7): 111233-111233
被引量:31
标识
DOI:10.1016/j.celrep.2022.111233
摘要
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.
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