Glutamine synthetase limits β-catenin-mutated liver cancer growth by maintaining nitrogen homeostasis and suppressing mTORC1.
Glutamine synthetase limits β-catenin-mutated liver cancer growth by maintaining nitrogen homeostasis and suppressing mTORC1.
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DOI：
10.1172/jci161408
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发表时间：
2022-12-15
影响因子：
15.9
通讯作者：
Zong, Wei-Xing
中科院分区：
文献类型：
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作者：
Dai, Weiwei;Shen, Jianliang;Yan, Junrong;Bott, Alex J.;Maimouni, Sara;Daguplo, Heineken Q.;Wang, Yujue;Khayati, Khoosheh;Guo, Jessie Yanxiang;Zhang, Lanjing;Wang, Yongbo;Valvezan, Alexander;Ding, Wen-Xing;Chen, Xin;Su, Xiaoyang;Gao, Shenglan;Zong, Wei-Xing
谷氨酰胺合成酶（GS）催化谷氨酰胺的重新合成，促进癌细胞的生长。在肝脏中，GS在尿素循环旁边起作用，去除氨废物。由于尿素循环失调与癌症发展有关，GS的氨清除功能在癌症中的影响尚未被探索。在这里，我们发现β-catenin（由CTNNB1编码）的致癌激活导致尿素循环减少和氨废物负担增加。虽然β-catenin诱导了GS的表达，这被认为是促进癌症的，但令人惊讶的是，在一些涉及β-catenin激活的小鼠模型中，肝脏GS的基因消融加速了肝脏肿瘤的发生。在机制上，GS消融加剧了高氨血症，促进了谷氨酸衍生的非必需氨基酸的产生，从而刺激了雷帕霉素复合物1 （mTORC1）的机制靶点。mTORC1和谷氨酸转氨酶的药理学和遗传学抑制抑制GS消融促进的肿瘤发生。虽然肝细胞癌患者，特别是CTNNB1突变患者，尿素循环整体缺陷和GS表达增加，但存在一小部分GS低表达的患者与mTORC1过度激活有关。因此，在含有β-catenin激活突变和尿素循环受损的肝脏中，gs介导的氨清除可作为肿瘤抑制机制。
Glutamine synthetase (GS) catalyzes de novo synthesis of glutamine that facilitates cancer cell growth. In the liver, GS functions next to the urea cycle to remove ammonia waste. As a dysregulated urea cycle is implicated in cancer development, the impact of GS’s ammonia clearance function has not been explored in cancer. Here, we show that oncogenic activation of β-catenin (encoded by CTNNB1) led to a decreased urea cycle and elevated ammonia waste burden. While β-catenin induced the expression of GS, which is thought to be cancer promoting, surprisingly, genetic ablation of hepatic GS accelerated the onset of liver tumors in several mouse models that involved β-catenin activation. Mechanistically, GS ablation exacerbated hyperammonemia and facilitated the production of glutamate-derived nonessential amino acids, which subsequently stimulated mechanistic target of rapamycin complex 1 (mTORC1). Pharmacological and genetic inhibition of mTORC1 and glutamic transaminases suppressed tumorigenesis facilitated by GS ablation. While patients with hepatocellular carcinoma, especially those with CTNNB1 mutations, have an overall defective urea cycle and increased expression of GS, there exists a subset of patients with low GS expression that is associated with mTORC1 hyperactivation. Therefore, GS-mediated ammonia clearance serves as a tumor-suppressing mechanism in livers that harbor β-catenin activation mutations and a compromised urea cycle.