Non-canonical role of UCKL1 on ferroptosis defence in colorectal cancer.
Non-canonical role of UCKL1 on ferroptosis defence in colorectal cancer.
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DOI：
10.1016/j.ebiom.2023.104650
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发表时间：
2023-07
期刊：
影响因子：
11.1
通讯作者：
Yuan, Ping
中科院分区：
文献类型：
--
作者：
Wu, Weili;Zhao, Yingying;Qin, Baifu;Jiang, Xin;Wang, Chuyue;Hu, Rong;Ma, Rui;Lee, Mong-Hong;Liu, Huanliang;Li, Kai;Yuan, Ping
嘧啶核苷酸促进结直肠癌（CRC）的生长，使其相关蛋白成为癌症干预的潜在靶点。尿苷-胞苷激酶样-1（UCKL 1）是一种参与嘧啶补救途径的酶。它在多种癌症中高度表达。但UCKL 1在结直肠癌中的作用及其机制尚不清楚。进行大规模基因组分析以搜索与嘧啶代谢相关的潜在CRC参与者。通过RNA干扰结合体内外实验检测UCKL 1在结直肠癌中的功能。通过GSH/GSSG测定、NADP+测定、ROS和脂质过氧化测定来检测UCKL 1在铁凋亡中的作用。通过代谢组学分析、RNA测序、蛋白质印迹和拯救试验来揭示UCKL 1的潜在机制。异种移植小鼠模型用于检查UCKL 1作为靶点与其他铁凋亡诱导剂组合的治疗潜力。UCKL 1被鉴定为抑制CRC细胞中的铁凋亡。在CRC中表达较高。它调节CRC细胞的增殖和迁移。UCKL 1的下调导致肿瘤脂质过氧化作用增强。有趣的是，UCKL 1还原介导的铁凋亡与其催化尿苷一磷酸（UMP）和胞苷一磷酸（CMP）合成的作用无关。相反，UCKL 1稳定了Nrf 2，这反过来又促进了SLC 7A 11（一种典型的铁凋亡抑制因子）的表达。此外，UCKL 1的下调在体外和体内使CRC细胞对GPX 4抑制剂敏感。我们的研究表明，UCKL 1通过UCKL 1-Nrf 2-SLC 7A 11轴在CRC细胞中抑制铁凋亡中发挥非经典作用。联合应用GPX 4抑制剂和UCKL 1靶向铁凋亡的治疗策略有望成为治疗结直肠癌的一种新的有效方法。本研究部分由基金（批准号31970674，PY）、（批准号2023 A1515030245，KL）、项目（2020 B1111170004）和。
Pyrimidine nucleotides fuel the growth of colorectal cancer (CRC), making their associated proteins potential targets for cancer intervention. Uridine-Cytidine Kinase Like-1(UCKL1) is an enzyme involved in the pyrimidine salvage pathway. It is highly expressed in multiple cancers. But the function and underlying mechanism of UCKL1 in CRC are yet to study. Large-scale genomic analysis was performed to search for potential CRC players related to pyrimidine metabolism. The function of UCKL1 in CRC were examined by RNA interference coupled with in vitro and in vivo assays. GSH/GSSG assay, NADP+ assay, ROS, and Lipid peroxidation assays were performed to check the function of UCKL1 in ferroptosis. Metabolomics analyses, RNA sequencing, western blotting, and rescue assays were done to reveal the underlying mechanisms of UCKL1. Xenograft mouse model was used to examine the therapeutic potential of UCKL1 as a target in combination with other ferroptosis inducers. UCKL1 was identified to repress ferroptosis in CRC cells. It was highly expressed in CRC. It regulated CRC cells proliferation and migration. Downregulation of UCKL1 led to enhanced tumour lipid peroxidation. Intriguingly, UCKL1 reduction-mediated ferroptosis was not related to its role in catalyzing uridine monophosphate (UMP) and cytidine monophosphate (CMP) synthesis. Instead, UCKL1 stabilized Nrf2, which in turn promoted the expression of SLC7A11, a classical repressor of ferroptosis. Moreover, downregulation of UCKL1 sensitized CRC cells to GPX4 inhibitors in vitro and in vivo. Our study demonstrates that UCKL1 plays a non-canonical role in repressing ferroptosis through a UCKL1-Nrf2-SLC7A11 axis in CRC cells. Combinatorial strategy in targeting ferroptosis by depletion of UCKL1 and application of GPX4 inhibitors may serve as a new effective method for CRC treatment. This study was supported in part by fund from (Grant No. 31970674 to PY), by the (Grant No. 2023A1515030245 to KL), by the program of (2020B1111170004), and by .
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影响因子：
14.8
作者：
Doll S;Proneth B;Tyurina YY;Panzilius E;Kobayashi S;Ingold I;Irmler M;Beckers J;Aichler M;Walch A;Prokisch H;Trümbach D;Mao G;Qu F;Bayir H;Füllekrug J;Scheel CH;Wurst W;Schick JA;Kagan VE;Angeli JP;Conrad M
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影响因子：
64.5
作者：
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影响因子：
50.3
作者：
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影响因子：
21.3
作者：
Friedmann Angeli JP;Schneider M;Proneth B;Tyurina YY;Tyurin VA;Hammond VJ;Herbach N;Aichler M;Walch A;Eggenhofer E;Basavarajappa D;Rådmark O;Kobayashi S;Seibt T;Beck H;Neff F;Esposito I;Wanke R;Förster H;Yefremova O;Heinrichmeyer M;Bornkamm GW;Geissler EK;Thomas SB;Stockwell BR;O'Donnell VB;Kagan VE;Schick JA;Conrad M
通讯作者：
Conrad M