Flavoxanthin Binds to AGR2 to Mediate Fatty Acid Oxidation and Reinforce Anoikis in Lung Adenocarcinoma

IF 3.5 4区医学 Q2 CHEMISTRY, MEDICINAL

Drug Development Research Pub Date : 2025-07-20 DOI:10.1002/ddr.70129

Meiling Sheng, Qunzhi Wang, Yabo Lou, Yuanchao Xiao, Xiaoming Wu

{"title":"Flavoxanthin Binds to AGR2 to Mediate Fatty Acid Oxidation and Reinforce Anoikis in Lung Adenocarcinoma","authors":"Meiling Sheng, Qunzhi Wang, Yabo Lou, Yuanchao Xiao, Xiaoming Wu","doi":"10.1002/ddr.70129","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n <p>Traditional Chinese medicine (TCM) can not only alleviate symptoms in cancer patients and improve their life quality but also serve as an adjuvant therapy to reduce the toxic side effects of chemotherapy and radiotherapy, making it a hot topic in anti-tumor drug development in recent years. This project was designed to probe into the small molecular Chinese medicine components with targeted effects on lung adenocarcinoma (LUAD) and further reveal their mechanisms. Based on The Cancer Genome Atlas dataset analysis of anterior gradient-2 (AGR2) expression in LUAD, Autodock docking and scoring were employed to screen small molecular drugs that bound to AGR2. The gene set enrichment analysis was utilized to analyze enriched pathways of AGR2. By utilizing the cellular thermal shift assay, the binding relationship between Flavoxanthin and AGR2 was validated. The expression of AGR2, long-chain acyl-CoA synthetase (ACSL1), and carnitine palmitoyltransferase 1A was detected by reverse transcription-quantitative polymerase chain reaction. The cell counting kit-8 was leveraged to determine the half maximal inhibitory concentration (IC<sub>50</sub>) and cell viability. Levels of fatty acid β-oxidation were measured, and BODIPY neutral lipid droplet staining was employed to evaluate fatty acid oxidation (FAO) intensity. The degree of anoikis was assessed by flow cytometry to detect apoptosis and western blot to detect anoikis-associated proteins. The immunohistochemistry was employed to measure the levels of Ki67 and Caspase-3. Tunel was applied to the detection of cell death. The result showed that flavoxanthin bound to highly-expressed AGR2 to reinforce anoikis in LUAD cells. Overexpression of AGR2 facilitated FAO inhibition of anoikis in LUAD. Flavoxanthin eliminated the promoting effect of AGR2 overexpression on FAO and restored the anoikis of LUAD cells. Animal experiments revealed that Flavoxanthin suppressed the malignant progression of LUAD through AGR2-mediated FAO. In conclusion, Flavoxanthin hinders FAO and boosts LUAD anoikis by targeting AGR2. These findings suggested that Flavoxanthin may be a novel option for intervention and treatment of LUAD, representing an instrumental advancement of small molecular components of TCM in modern oncology.</p>\n </section>\n </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 5","pages":""},"PeriodicalIF":3.5000,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Development Research","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ddr.70129","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Traditional Chinese medicine (TCM) can not only alleviate symptoms in cancer patients and improve their life quality but also serve as an adjuvant therapy to reduce the toxic side effects of chemotherapy and radiotherapy, making it a hot topic in anti-tumor drug development in recent years. This project was designed to probe into the small molecular Chinese medicine components with targeted effects on lung adenocarcinoma (LUAD) and further reveal their mechanisms. Based on The Cancer Genome Atlas dataset analysis of anterior gradient-2 (AGR2) expression in LUAD, Autodock docking and scoring were employed to screen small molecular drugs that bound to AGR2. The gene set enrichment analysis was utilized to analyze enriched pathways of AGR2. By utilizing the cellular thermal shift assay, the binding relationship between Flavoxanthin and AGR2 was validated. The expression of AGR2, long-chain acyl-CoA synthetase (ACSL1), and carnitine palmitoyltransferase 1A was detected by reverse transcription-quantitative polymerase chain reaction. The cell counting kit-8 was leveraged to determine the half maximal inhibitory concentration (IC₅₀) and cell viability. Levels of fatty acid β-oxidation were measured, and BODIPY neutral lipid droplet staining was employed to evaluate fatty acid oxidation (FAO) intensity. The degree of anoikis was assessed by flow cytometry to detect apoptosis and western blot to detect anoikis-associated proteins. The immunohistochemistry was employed to measure the levels of Ki67 and Caspase-3. Tunel was applied to the detection of cell death. The result showed that flavoxanthin bound to highly-expressed AGR2 to reinforce anoikis in LUAD cells. Overexpression of AGR2 facilitated FAO inhibition of anoikis in LUAD. Flavoxanthin eliminated the promoting effect of AGR2 overexpression on FAO and restored the anoikis of LUAD cells. Animal experiments revealed that Flavoxanthin suppressed the malignant progression of LUAD through AGR2-mediated FAO. In conclusion, Flavoxanthin hinders FAO and boosts LUAD anoikis by targeting AGR2. These findings suggested that Flavoxanthin may be a novel option for intervention and treatment of LUAD, representing an instrumental advancement of small molecular components of TCM in modern oncology.

查看原文本刊更多论文

黄黄素与AGR2结合介导肺腺癌中脂肪酸氧化并增强抗氧化作用

中药不仅可以缓解癌症患者的症状，提高患者的生活质量，而且还可以作为一种辅助治疗方法，减少化疗和放疗的毒副作用，是近年来抗肿瘤药物开发的热点。本项目旨在探索靶向治疗肺腺癌（LUAD）的中药小分子成分，并进一步揭示其作用机制。基于Cancer Genome Atlas数据集对LUAD中AGR2表达的分析，采用Autodock对接和评分方法筛选结合AGR2的小分子药物。基因集富集分析用于分析AGR2的富集途径。利用细胞热移法验证了黄黄素与AGR2的结合关系。逆转录-定量聚合酶链反应检测AGR2、长链酰基辅酶a合成酶（ACSL1）和肉毒碱棕榈酰基转移酶1A的表达。利用细胞计数试剂盒-8测定最大半数抑制浓度（IC50）和细胞活力。测定脂肪酸β-氧化水平，采用BODIPY中性脂滴染色法评价脂肪酸氧化（FAO）强度。采用流式细胞术检测细胞凋亡，western blot检测anoiosis相关蛋白。免疫组化法检测Ki67和Caspase-3的表达水平。采用隧道法检测细胞死亡。结果表明，黄黄素与高表达的AGR2结合可增强LUAD细胞的抗氧化能力。AGR2的过表达促进了FAO对LUAD中anoikis的抑制。黄黄素消除了AGR2过表达对FAO的促进作用，恢复了LUAD细胞的活力。动物实验表明黄黄素通过agr2介导的FAO抑制LUAD的恶性进展。综上所述，黄黄素通过靶向AGR2抑制FAO并促进LUAD的发生。这些发现表明黄黄素可能是干预和治疗LUAD的新选择，代表了中医小分子成分在现代肿瘤学中的重要进展。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Drug Development Research 医学-药学

CiteScore

6.40

自引率

2.60%

发文量

104

审稿时长

6-12 weeks

期刊介绍： Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.