State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Department of Hepatobiliary, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
Cancer Res. 2024 May 15;84(10):1643-1658. doi: 10.1158/0008-5472.CAN-23-0673.
Hepatocellular carcinoma (HCC) is a typical tumor that undergoes metabolic reprogramming, differing from normal liver tissue in glucose, lipid, nucleic acid, and amino acid metabolism. Although ammonia is a toxic metabolic by-product, it has also been recently recognized as a signaling molecule to activate lipid metabolism, and it can be a nitrogen source for biosynthesis to support tumorigenesis. In this study, we revealed that β-catenin activation increases ammonia production in HCC mainly by stimulating glutaminolysis. β-Catenin/LEF1 activated the transcription of the glutamate dehydrogenase GLUD1, which then promoted ammonia utilization to enhance the production of glutamate, aspartate, and proline as evidenced by 15NH4Cl metabolic flux. β-Catenin/TCF4 induced the transcription of SLC4A11, an ammonia transporter, to excrete excess ammonia. SLC4A11 was upregulated in HCC tumor tissues, and high SLC4A11 expression was associated with poor prognosis and advanced disease stages. Loss of SLC4A11 induced HCC cell senescence in vitro by blocking ammonia excretion and reduced β-catenin-driven tumor growth in vivo. Furthermore, elevated levels of plasma ammonia promoted the progression of β-catenin mutant HCC, which was impeded by SLC4A11 deficiency. Downregulation of SLC4A11 led to ammonia accumulation in tumor interstitial fluid and decreased plasma ammonia levels in HCC with activated β-catenin. Altogether, this study indicates that β-catenin activation reprograms ammonia metabolism and that blocking ammonia excretion by targeting SLC4A11 could be a promising approach to induce senescence in β-catenin mutant HCC.
Ammonia metabolism reprogramming mediated by aberrant activation of β-catenin induces resistance to senescence in HCC and can be targeted by inhibiting SLC4A11 as a potential therapy for β-catenin mutant liver cancer.
肝细胞癌（HCC）是一种典型的肿瘤，其经历代谢重编程，在葡萄糖、脂质、核酸和氨基酸代谢方面与正常肝组织不同。尽管氨是一种有毒的代谢副产物，但它最近也被认为是一种信号分子，可激活脂质代谢，并且可以作为氮源支持肿瘤发生的生物合成。在这项研究中，我们揭示了β-连环蛋白（β-catenin）的激活主要通过刺激谷氨酰胺分解作用增加 HCC 中的氨产生。β-catenin/LEF1 激活谷氨酸脱氢酶 GLUD1 的转录，从而促进氨的利用，以增强谷氨酸、天冬氨酸和脯氨酸的产生，这一点通过 15NH4Cl 代谢通量得到证明。β-catenin/TCF4 诱导氨转运蛋白 SLC4A11 的转录，以排出多余的氨。SLC4A11 在 HCC 肿瘤组织中上调，并且高 SLC4A11 表达与不良预后和晚期疾病阶段相关。体外 SLC4A11 的缺失会通过阻断氨排泄诱导 HCC 细胞衰老，并在体内降低β-catenin 驱动的肿瘤生长。此外，血浆氨水平升高促进了β-catenin 突变 HCC 的进展，而 SLC4A11 的缺失则阻碍了其进展。SLC4A11 的下调导致肿瘤间质液中氨的积累，并降低了 HCC 中β-catenin 激活时的血浆氨水平。总的来说，这项研究表明β-catenin 的激活重新编程了氨代谢，通过靶向 SLC4A11 阻断氨排泄可能是诱导β-catenin 突变 HCC 衰老的一种有前途的方法。
异常激活的β-catenin 介导的氨代谢重编程诱导 HCC 对衰老产生抗性，并可通过抑制 SLC4A11 作为β-catenin 突变肝癌的潜在治疗靶点。
