Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
Cell Rep. 2022 Aug 16;40(7):111233. doi: 10.1016/j.celrep.2022.111233.
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.
5-氟尿嘧啶（5-FU）是结直肠癌（CRC）化疗的关键组成部分。5-FU 的疗效取决于叶酸辅助因子的细胞内水平和 DNA 损伤修复策略。然而，耐药性仍然是一个主要挑战。在这里，我们报告丝氨酸代谢的改变会影响体外和体内 CRC 模型中 5-FU 的敏感性。特别是，5-FU 耐药的 CRC 细胞通过上调内源性丝氨酸合成或增加外源性丝氨酸摄取来表现出强烈的丝氨酸依赖性。重要的是，无论采用哪种丝氨酸喂养策略，丝氨酸羟甲基转移酶 2（SHMT2）驱动的一碳代谢在线粒体中的区室化都是耐药细胞的一种特定适应，以支持嘌呤生物合成并增强 DNA 损伤反应。干扰丝氨酸的可用性或影响其线粒体代谢会逆转 5-FU 的耐药性。这些数据揭示了一种与线粒体丝氨酸利用相关的机制，该机制支持 CRC 中 5-FU 的耐药性，并为治疗方法提供了新的思路。
