Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations
Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations
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DOI：
10.1016/j.cmet.2019.01.002
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发表时间：
2019-05-07
期刊：
影响因子：
29
通讯作者：
Monga, Satdarshan P.
中科院分区：
文献类型：
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作者：
Michael, Adeola O. Adebayo;Ko, Sungjin;Monga, Satdarshan P.
基于其小叶位置，肝细胞显示差异基因表达，包括围绕中央静脉的中央周围肝细胞，其由Wnt-β-连环蛋白信号传导标记。激活β-连环蛋白突变发生在各种肝脏肿瘤中，包括肝细胞癌（HCC），但没有特异性疗法可用于治疗这些肿瘤亚群。在这里，我们确定了β-连环蛋白激活，其转录靶谷氨酰胺合成酶（GS），和p-mTOR-S2448，mTORC 1激活的指标之间的正相关关系。在小鼠和人类的正常肝脏中，中央周围肝细胞同时为GS和p-mTOR-S2448阳性，β-连环蛋白突变的肝脏肿瘤也是如此。β-连环蛋白信号传导或GS的遗传破坏阻止p-mTOR-S2448表达，而其在β-连环蛋白缺陷肝脏中的强制表达导致异位p-mTOR-S2448表达。此外，我们发现mTORC 1抑制通过抑制细胞增殖和存活在muplasma-β-catenin驱动的HCC中具有显著的治疗益处。因此，mTORC 1抑制剂可能与β-连环蛋白突变和GS阳性的肝肿瘤的治疗高度相关。
Based on their lobule location, hepatocytes display differential gene expression, including pericentral hepatocytes that surround the central vein, which are marked by Wnt-beta-catenin signaling. Activating beta-catenin mutations occur in a variety of liver tumors, including hepatocellular carcinoma (HCC), but no specific therapies are available to treat these tumor subsets. Here, we identify a positive relationship between beta-catenin activation, its transcriptional target glutamine synthetase (GS), and p-mTOR-S2448, an indicator of mTORC1 activation. In normal livers of mice and humans, pericentral hepatocytes were simultaneously GS and p-mTOR-S2448 positive, as were beta-catenin-mutated liver tumors. Genetic disruption of beta-catenin signaling or GS prevented p-mTOR-S2448 expression, while its forced expression in beta-catenin-deficient livers led to ectopic p-mTOR-S2448 expression. Further, we found notable therapeutic benefit of mTORC1 inhibition in mutant-beta-catenin-driven HCC through suppression of cell proliferation and survival. Thus, mTORC1 inhibitors could be highly relevant in the treatment of liver tumors that are beta-catenin mutated and GS positive.