Liu Cong, Jiang Junguang, Luo Junfang, Zhang Yang, Yang Chao, Shi Jiang
Department of Geriatric Respiratory & Sleep, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Apr;398(4):4633-4643. doi: 10.1007/s00210-024-03574-x. Epub 2024 Nov 9.
Non-small cell lung cancer (NSCLC) is a common malignant tumor characterized by rapid growth and invasive power. Glucose regulatory protein 78 (GRP78) is important in cancer cell progression. Here, this study aimed to explore the effect and mechanism of GRP78 on cisplatin (DDP) resistance of NSCLC cells. qRT-PCR and Western blot detected the expression of genes and proteins. Flow cytometry was used to analyze endoplasmic reticulum stress (ERS) induced by DDP in NSCLC. Cell proliferation and apoptosis were examined using cell counting kit-8 (CCK8), cell cloning, and flow cytometry, respectively. Chromatin immunoprecipitation assay (CHIP) and dual-luciferase reporter assays were performed to determine the binding of ETS1 and GRP78 promoter. Mouse xenograft models were constructed for in vivo analysis. ERS was induced by DDP in NSCLC cells. GRP78 were upregulated in DDP-resistant NSCLC tissues, and knockdown of GRP78 suppressed DDP resistance, clone formation, promoted apoptosis, and inhibited ERS in DDP-resistant NSCLC cells. ETS1 knockdown repressed GRP78 expression and NSCLC tumor growth. Interestingly, ETS1 played a role in DDP-resistant NSCLC via GRP78. ETS1 inhibits cisplatin sensitivity of NSCLC cells by promoting GRP78 transcription.
非小细胞肺癌（NSCLC）是一种常见的恶性肿瘤，其特征是生长迅速且具有侵袭性。葡萄糖调节蛋白78（GRP78）在癌细胞进展中起重要作用。在此，本研究旨在探讨GRP78对NSCLC细胞顺铂（DDP）耐药性的影响及机制。qRT-PCR和蛋白质印迹法检测基因和蛋白质的表达。流式细胞术用于分析DDP在NSCLC中诱导的内质网应激（ERS）。分别使用细胞计数试剂盒-8（CCK8）、细胞克隆和流式细胞术检测细胞增殖和凋亡。进行染色质免疫沉淀分析（CHIP）和双荧光素酶报告基因检测以确定ETS1与GRP78启动子的结合。构建小鼠异种移植模型用于体内分析。DDP在NSCLC细胞中诱导ERS。GRP78在耐DDP的NSCLC组织中上调，敲低GRP78可抑制耐DDP的NSCLC细胞的DDP耐药性、克隆形成，促进凋亡并抑制ERS。敲低ETS1可抑制GRP78表达和NSCLC肿瘤生长。有趣的是，ETS1通过GRP78在耐DDP的NSCLC中发挥作用。ETS1通过促进GRP78转录抑制NSCLC细胞对顺铂的敏感性。
