Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
Eur J Pharmacol. 2024 Nov 15;983:177002. doi: 10.1016/j.ejphar.2024.177002. Epub 2024 Sep 16.
Gastric cancer (GC) is a common malignant disease that has a fifth highest incidence and fourth highest mortality worldwide. The Warburg effect is a common phenomenon observed in tumors, which suggests that tumor cells would enhance glucose uptake by overexpressing multiple glucose transporters. Sodium glucose transporter 2 (SGLT2) is one of glucose transporters which highly expressed in several cancers, but its role in gastric cancer is still unclear. Our research found that there was a high expression level of SGLT2 in gastric cancer tissues. We found that Dapagliflozin (a SGLT2 inhibitor) could suppress gastric cancer cell proliferation and migration in vitro and tumor growth in vivo. In present study, we revealed how dapagliflozin would suppress gastric cancer progression in a novel mechanism. We proved that dapagliflozin decreased the expression level of OTU deubiquitinase 5 (OTUD5), which further increased the ubiquitination and degradation of YAP1. Overexpression of OTUD5 in gastric cancer cells partly reversed the anti-tumor effect of dapagliflozin. Our findings revealed a novel mechanism by which dapagliflozin has an antitumor effect on gastric cancer and proposed a beneficial strategy for the application of dapagliflozin in gastric cancer patients.
胃癌（GC）是一种常见的恶性疾病，其发病率在全球范围内排名第五，死亡率排名第四。瓦博格效应是肿瘤中常见的现象，表明肿瘤细胞通过过度表达多种葡萄糖转运蛋白来增强葡萄糖摄取。钠-葡萄糖协同转运蛋白 2（SGLT2）是在几种癌症中高度表达的葡萄糖转运蛋白之一，但它在胃癌中的作用尚不清楚。我们的研究发现 SGLT2 在胃癌组织中有高表达水平。我们发现达格列净（一种 SGLT2 抑制剂）可以在体外抑制胃癌细胞增殖和迁移，在体内抑制肿瘤生长。在本研究中，我们揭示了达格列净如何通过一种新的机制抑制胃癌的进展。我们证明达格列净降低了 OTU 去泛素化酶 5（OTUD5）的表达水平，这进一步增加了 YAP1 的泛素化和降解。在胃癌细胞中过表达 OTUD5 部分逆转了达格列净的抗肿瘤作用。我们的研究结果揭示了达格列净对胃癌具有抗肿瘤作用的新机制，并为达格列净在胃癌患者中的应用提出了有益的策略。
