小柯机器人

中山大学Shuzhong Yao、Chaoyun Pan、Junxiu Liu和Jie Li合作在研究中取得进展。他们发现酪氨酸代谢通过抑制上皮性卵巢癌（EOC）细胞中转座子DNA的合成来增强基因毒性化疗的效果。这一研究成果发表在2023年10月16日出版的国际学术期刊《细胞-代谢》上。

研究人员发现了富马酸乙酰乙酸水解酶（FAH）（催化酪氨酸分解代谢最后一步的酶）的缺乏会降低上皮性卵巢癌的化疗敏感性。FAH的表达水平与EOC患者的化疗效果密切相关。从机理上讲，在基因毒性化疗的作用下，FAH在Met308处被氧化并转移到细胞核中，FAH介导的酪氨酸代谢主要为细胞核提供富马酸。FAH产生的富马酸直接与REV1结合，从而抑制转座子DNA合成（TLS）并提高化疗敏感性。

此外，体内补充酪氨酸可提高对基因毒性化疗药物的敏感性，减少耐药性的发生。该研究结果揭示了来源于酪氨酸的富马酸盐在TLS调控中的独特作用，提示可通过膳食补充酪氨酸来改善基因毒性化疗。

据了解，氨基酸代谢作为抗肿瘤治疗的一个潜在靶点已得到广泛研究，但它如何改变基因毒性化疗反应仍是未知。

附：英文原文

Title: Tyrosine catabolism enhances genotoxic chemotherapy by suppressing translesion DNA synthesis in epithelial ovarian cancer

Author: Jie Li, Cuimiao Zheng, Qiuwen Mai, Xi Huang, Wenfeng Pan, Jingyi Lu, Zhengfan Chen, Suman Zhang, Chunyu Zhang, Hua Huang, Yangyang Chen, Hongbo Guo, Zhenyin Wu, Chunnuan Deng, Yiting Jiang, Bo Li, Junxiu Liu, Shuzhong Yao, Chaoyun Pan

Issue&Volume: 2023-10-16

Abstract: Amino acid metabolism has been actively investigated as a potential target for antitumortherapy, but how it may alter the response to genotoxic chemotherapy remains largelyunknown. Here, we report that the depletion of fumarylacetoacetate hydrolase (FAH),an enzyme that catalyzes the final step of tyrosine catabolism, reduced chemosensitivityin epithelial ovarian cancer (EOC). The expression level of FAH correlated significantlywith chemotherapy efficacy in patients with EOC. Mechanistically, under genotoxicchemotherapy, FAH is oxidized at Met308 and translocates to the nucleus, where FAH-mediatedtyrosine catabolism predominantly supplies fumarate. FAH-produced fumarate binds directlyto REV1, resulting in the suppression of translesion DNA synthesis (TLS) and improvedchemosensitivity. Furthermore, in vivo tyrosine supplementation improves sensitivity to genotoxic chemotherapeutics andreduces the occurrence of therapy resistance. Our findings reveal a unique role fortyrosine-derived fumarate in the regulation of TLS and may be exploited to improvegenotoxic chemotherapy through dietary tyrosine supplementation.

DOI: 10.1016/j.cmet.2023.10.002

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00371-6

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