Wang Lei, Fang Zhiyu, Gao Peixiang, Zheng Junfang
Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Front Oncol. 2022 Sep 20;12:975517. doi: 10.3389/fonc.2022.975517. eCollection 2022.
Growing cancer cells are addicted to glutamine. Glutamate dehydrogenase 1 (GLUD1) is one of key enzymes in glutamine metabolism and plays a critical role in the malignancy of diverse tumors. However, its role and molecular mechanism in clear cell renal cell carcinoma (ccRCC) development and progression remain unknown. In this study, analysis results of the GEO/TCGA/UALCAN database showed that GLUD1 level was downregulated in ccRCC tissues. Immunohistochemistry and western blotting results further validated the downregulation of GLUD1 level in ccRCC tissues. GLUD1 level was gradually decreased as ccRCC stage and grade progressed. Low GLUD1 level was associated with a shorter survival and higher IC50 value for tyrosine kinase inhibitors (TKIs) in ccRCC, reminding that GLUD1 level could predict the prognosis and TKIs sensitivity of ccRCC patients. High level of methylation in promoter was positively correlated with the downregulation of GLUD1 level and was negatively correlated with survival of ccRCC patients. GLUD1 overexpression suppressed RCC cell proliferation, colony formation and migration by inhibiting PI3K/Akt/mTOR pathway activation. Low GLUD1 level correlated with suppressive immune microenvironment (TIME) in ccRCC. Together, we found a novel tumor-suppressing role of GLUD1 in ccRCC which was different from that in other tumors and a new mechanism for inhibiting PI3K/Akt/mTOR activation and TIME in ccRCC. These results provide a theoretical basis for GLUD1 as a therapeutic target and prognostic marker in ccRCC.
不断生长的癌细胞对谷氨酰胺有依赖性。谷氨酸脱氢酶1（GLUD1）是谷氨酰胺代谢中的关键酶之一，在多种肿瘤的恶性发展中起关键作用。然而，其在透明细胞肾细胞癌（ccRCC）发生发展中的作用及分子机制仍不清楚。在本研究中，GEO/TCGA/UALCAN数据库的分析结果显示，ccRCC组织中GLUD1水平下调。免疫组织化学和蛋白质印迹结果进一步验证了ccRCC组织中GLUD1水平的下调。随着ccRCC分期和分级的进展，GLUD1水平逐渐降低。低GLUD1水平与ccRCC患者较短的生存期和较高的酪氨酸激酶抑制剂（TKIs）半数抑制浓度（IC50）值相关，提示GLUD1水平可预测ccRCC患者的预后和TKIs敏感性。启动子区域的高甲基化水平与GLUD1水平的下调呈正相关，与ccRCC患者的生存期呈负相关。GLUD1过表达通过抑制PI3K/Akt/mTOR通路激活来抑制肾癌细胞的增殖、集落形成和迁移。低GLUD1水平与ccRCC中免疫抑制性微环境（TIME）相关。我们共同发现了GLUD1在ccRCC中具有不同于其他肿瘤的新型肿瘤抑制作用，以及抑制ccRCC中PI3K/Akt/mTOR激活和TIME的新机制。这些结果为GLUD1作为ccRCC的治疗靶点和预后标志物提供了理论依据。
