Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China; Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
Biochem Pharmacol. 2021 Jun;188:114525. doi: 10.1016/j.bcp.2021.114525. Epub 2021 Mar 17.
The dysregulation of glycolysis leads to serials of disease. Rabeprazole is a representative of proton pump inhibitors and widely used in anti-ulcer treatment. However, the function of Rabeprazole on glycolysis in gastric epithelial cells remained to be identified. In this study, 30（Helicobacter pylori）H. pylori-negative cases and 26H. pylori-positive cases treated with Rabeprazole were recruited. The qPCR and Western blotting results showed that Rabeprazole suppressed cell proliferation by inhibition of HK2-mediated glycolysis in BGC823 cells, leading to decrease glucose uptake and lactate production in a dose-dependent way. Furthermore, the phosphorylation of signal transducer and activator of transcription 3 (STAT3) was drastically reduced in response to Rabeprazole stimulation, leading to attenuate STAT3 nuclear translocation. Luciferase and Chromatin immunoprecipitation (ChIP) analysis showed that Rabeprazole treatment led to a significant inhibition of the binding of STAT3 to the promoter of the HK2 gene, repressing transcriptional activation of HK2. Moreover, the ectopic expression of STAT3 in BGC823 cells resulted in recovery of HK2 transactivation and cell proliferation in Rabeprazole-treated cells. Most importantly, HK2 expression was significantly increased in H. pylori-infected gastric mucosa. These findings suggested that Rabeprazole inhibited cell proliferation by targeting STAT3/HK2 signaling-mediated glucose metabolism in gastric epithelial cells. Therefore, targeting HK2 is an alternative strategy in improving the treatment of patients with H. pylori infection.
糖酵解失调会导致一系列疾病。雷贝拉唑是质子泵抑制剂的代表药物，广泛用于抗溃疡治疗。然而，雷贝拉唑对胃上皮细胞糖酵解的作用尚待确定。在这项研究中，招募了 30 例（幽门螺杆菌）H. pylori 阴性病例和 26 例 H. pylori 阳性病例，用雷贝拉唑治疗。qPCR 和 Western blot 结果表明，雷贝拉唑通过抑制 HK2 介导的 BGC823 细胞糖酵解来抑制细胞增殖，从而导致葡萄糖摄取和乳酸生成呈剂量依赖性下降。此外，雷贝拉唑刺激导致信号转导和转录激活因子 3（STAT3）的磷酸化急剧减少，导致 STAT3 核易位减弱。荧光素酶和染色质免疫沉淀（ChIP）分析表明，雷贝拉唑处理导致 STAT3 与 HK2 基因启动子结合显著抑制，抑制 HK2 的转录激活。此外，BGC823 细胞中 STAT3 的异位表达导致雷贝拉唑处理细胞中 HK2 反式激活和细胞增殖的恢复。最重要的是，在 H. pylori 感染的胃黏膜中 HK2 的表达明显增加。这些发现表明，雷贝拉唑通过靶向 STAT3/HK2 信号转导介导的胃上皮细胞糖代谢抑制细胞增殖。因此，靶向 HK2 是改善 H. pylori 感染患者治疗的一种替代策略。
