Oncogenic β-catenin stimulation of AKT2-CAD-mediated pyrimidine synthesis is targetable vulnerability in liver cancer.
Oncogenic β-catenin stimulation of AKT2-CAD-mediated pyrimidine synthesis is targetable vulnerability in liver cancer.
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AKT2-CAD 介导的嘧啶合成的致癌β-连环蛋白刺激是肝癌中的目标脆弱性
DOI：
10.1073/pnas.2202157119
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发表时间：
2022-09-27
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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作者：
β-Catenin编码基因CTNNB 1是肝癌中突变频率最高的原癌基因。我们报道了活性β-连环蛋白在肝癌发生的起始和进展中是必不可少的。β-catenin作为AKT 2的转录激活因子，增强CAD的AKT 2磷酸化，其反过来刺激嘧啶从头合成和肝癌发展。β-连环蛋白、AKT 2和嘧啶合成抑制剂是治疗致癌β-连环蛋白相关癌症的有前景的治疗剂。CTNNB 1编码β-catenin蛋白，是肝肿瘤中最常见的原癌基因。本研究旨在探讨CTNNB 1功能获得性突变在肝癌发生中的意义及其病理机制。在小鼠模型中，活化的β-catenin不仅触发了肝肿瘤的发生，而且还加剧了TP 53缺失或B病毒感染介导的肝癌的发展。使用非靶向代谢组学分析，我们确定促进从头嘧啶合成为β-连环蛋白突变细胞系和肝脏中的主要代谢畸变。致癌β-连环蛋白转录刺激AKT 2，然后磷酸化S1406和S1859上的限速从头嘧啶合成酶CAD（氨甲酰磷酸合成酶2，天冬氨酸转氨甲酰酶，二氢乳清酸酶），以增强核苷酸合成。此外，抑制β-catenin/AKT 2刺激的嘧啶合成轴优先抑制β-catenin突变细胞增殖和肿瘤形成。因此，β-连环蛋白活性突变在各种临床前肝癌模型中是致癌的。刺激β-连环蛋白/AKT 2/CAD信号级联反应对嘧啶合成的影响是β-连环蛋白突变肝癌的一个重要且可药物治疗的弱点。
β-Catenin encoding gene CTNNB1 is known as the most frequently mutated proto-oncogene in liver cancer. We report that active β-catenin is essential in initiation and advancement of hepatocarcinogenesis. As a transcriptional activator of AKT2, β-catenin potentiates AKT2 phosphorylation of CAD, which in return stimulates de novo pyrimidine synthesis and liver cancer development. β-Catenin, AKT2, and pyrimidine synthesis inhibitors are promising therapeutics for the treatment of oncogenic β-catenin–associated cancer. CTNNB1, encoding β-catenin protein, is the most frequently altered proto-oncogene in hepatic neoplasms. In this study, we studied the significance and pathological mechanism of CTNNB1 gain-of-function mutations in hepatocarcinogenesis. Activated β-catenin not only triggered hepatic tumorigenesis but also exacerbated Tp53 deletion or hepatitis B virus infection–mediated liver cancer development in mouse models. Using untargeted metabolomic profiling, we identified boosted de novo pyrimidine synthesis as the major metabolic aberration in β-catenin mutant cell lines and livers. Oncogenic β-catenin transcriptionally stimulated AKT2, which then phosphorylated the rate-limiting de novo pyrimidine synthesis enzyme CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase) on S1406 and S1859 to potentiate nucleotide synthesis. Moreover, inhibition of β-catenin/AKT2-stimulated pyrimidine synthesis axis preferentially repressed β-catenin mutant cell proliferation and tumor formation. Therefore, β-catenin active mutations are oncogenic in various preclinical liver cancer models. Stimulation of β-catenin/AKT2/CAD signaling cascade on pyrimidine synthesis is an essential and druggable vulnerability for β-catenin mutant liver cancer.
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影响因子：
5.1
作者：
Chen, Wan-qing;Zeng, Hong-mei;He, Jie
通讯作者：
He, Jie
影响因子：
24.5
作者：
Farges, Olivier;Ferreira, Nelio;Paradis, Valerie
通讯作者：
Paradis, Valerie
影响因子：
5.2
作者：
Weir GM;Liwski RS;Mansour M
通讯作者：
Mansour M
影响因子：
64.5
作者：
CHISARI, FV;KLOPCHIN, K;PALMITER, RD
通讯作者：
PALMITER, RD
影响因子：
29.4
作者：
Katz, Sarah-Fee;Lechel, Andre;Rudolph, K. Lenhard
通讯作者：
Rudolph, K. Lenhard