Department of Cardiothoracic Surgery, Nanping First Hospital Affiliated to Fujian Medical University, Nanping, 353000, China.
Disinfection Supply Center, Nanping First Hospital Affiliated to Fujian Medical University, Nanping, 353000, China.
Pharmacogenomics J. 2024 Nov 5;24(6):33. doi: 10.1038/s41397-024-00355-w.
Cisplatin is widely used as a conventional chemotherapy drug for lung adenocarcinoma (LUAD) patients. However, the chemical resistance greatly limits its therapeutic potential. The study aimed to uncover the specific role and new mechanisms of CPT1B in the cisplatin resistance of LUAD. Bioinformatics analysis was utilized to analyze the expression level and enriched pathway of CPT1B in LUAD. The expression of CPT1B in LUAD cells was determined by utilizing quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot (WB). The cisplatin resistance in LUAD was measured with IC values obtained from the CCK-8 assay. We used the corresponding reagent kit and WB analysis to determine the levels of triglycerides, cholesterol, phospholipids, fatty acid β-oxidation (FAO) rate, and expression of lipid metabolism-related proteins. Finally, the regulation relationship between CPT1B and ZNF263 was confirmed through bioinformatics analysis, dual-luciferase, and chromatin immunoprecipitation assays. The present investigation revealed that CPT1B was upregulated in LUAD, participating in fatty acid metabolism pathways. In vitro studies have shown that upregulation of CPT1B promoted cisplatin resistance in LUAD cells. This promotion effect induced by the high expression of CPT1B on cisplatin resistance in LUAD was weakened after the addition of the FAO inhibitor Etomoxir. Mechanistically, ZNF263 was capable of binding to the promoter of CPT1B to activate its transcription, thereby enhancing FAO and promoting cisplatin resistance in LUAD cells. In summary, ZNF263 enhances cisplatin resistance in LUAD cells by upregulating CPT1B expression. This study enriches the molecular mechanisms of LUAD chemotherapy resistance and provides new directions for exploring therapeutic targets for LUAD.
顺铂被广泛用作肺腺癌 (LUAD) 患者的常规化疗药物。然而，其化学耐药性极大地限制了其治疗潜力。本研究旨在揭示 CPT1B 在 LUAD 顺铂耐药中的特定作用和新机制。利用生物信息学分析方法分析 CPT1B 在 LUAD 中的表达水平和富集通路。通过定量逆转录聚合酶链反应 (qRT-PCR) 和蛋白质印迹 (WB) 测定 LUAD 细胞中 CPT1B 的表达。利用 CCK-8 测定法获得的 IC 值测定 LUAD 的顺铂耐药性。我们使用相应的试剂盒和 WB 分析来测定甘油三酯、胆固醇、磷脂、脂肪酸 β-氧化 (FAO) 率和脂质代谢相关蛋白的表达水平。最后，通过生物信息学分析、双荧光素酶报告基因实验和染色质免疫沉淀实验证实了 CPT1B 与 ZNF263 之间的调控关系。本研究揭示了 CPT1B 在 LUAD 中上调，参与脂肪酸代谢途径。体外研究表明，CPT1B 的上调促进了 LUAD 细胞对顺铂的耐药性。在添加 FAO 抑制剂 Etomoxir 后，CPT1B 高表达对 LUAD 顺铂耐药性的促进作用减弱。在机制上，ZNF263 能够与 CPT1B 的启动子结合，激活其转录，从而增强 FAO 并促进 LUAD 细胞对顺铂的耐药性。总之，ZNF263 通过上调 CPT1B 的表达增强 LUAD 细胞的顺铂耐药性。本研究丰富了 LUAD 化疗耐药的分子机制，为探索 LUAD 的治疗靶点提供了新方向。
