Jinsheng Ding , Yongjie Xie , Ziyun Liu , Zhaoyu Zhang , Bo Ni , Jingrui Yan , Tianxing Zhou , Jihui Hao
{"title":"缺氧和酸性肿瘤微环境驱动的 AVL9 通过 AVL9-IκBα-SKP1 复合物促进胰腺导管腺癌的化疗抗性","authors":"Jinsheng Ding , Yongjie Xie , Ziyun Liu , Zhaoyu Zhang , Bo Ni , Jingrui Yan , Tianxing Zhou , Jihui Hao","doi":"10.1053/j.gastro.2024.10.042","DOIUrl":null,"url":null,"abstract":"<div><h3>Background & Aims</h3><div>Gemcitabine combined with albumin-paclitaxel (AG) is a crucial therapeutic option for pancreatic ductal adenocarcinoma (PDAC). However, the response to chemotherapy is relatively poor, with rapid development of resistance. The aim of this study was to explore the mechanism of resistance to AG and to develop strategies that can sensitize the AG regimen.</div></div><div><h3>Methods</h3><div>We used organoid models, patient-derived xenografts, and genetically engineered mouse models in our study. Chromatin immunoprecipitation, double luciferase assay, co-immunoprecipitation, and far-western blotting analysis were performed to investigate the mechanism. The AVL9 inhibitors were identified through protein structure analysis and molecular docking analysis, and their efficacy was verified in patient-derived xenografts, patient-derived organoids-based xenograft, and KPC models.</div></div><div><h3>Results</h3><div>Through multistrategy screening, we identified AVL9 as a key target for AG resistance in PDAC. Its tumor-promoting effects were confirmed in our clinical cohorts. Mechanistically, HIF-1α, a hypoxia-related transcription factor, drives the expression of AVL9. AVL9 acts as a scaffold that facilitates the binding of IκBα to SKP1, leading to enhanced ubiquitination and degradation of IκBα, which further activates the nuclear factor–κB pathway. The potential AVL9-targeting inhibitor, Edotecarin, was shown to reverse AG chemo-resistance in PDAC.</div></div><div><h3>Conclusion</h3><div>AVL9 expression is driven by HIF-1α in PDAC. The physical interaction of AVL9, IκBα, and SKP1 provides a novel molecular mechanism for the abnormal activation of the nuclear factor–κB pathway. Therefore, the AVL9-targeting drug Edotecarin could be a promising therapeutic strategy for sensitizing PDAC to AG.</div></div>","PeriodicalId":12590,"journal":{"name":"Gastroenterology","volume":"168 3","pages":"Pages 539-555.e5"},"PeriodicalIF":25.7000,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Hypoxic and Acidic Tumor Microenvironment–Driven AVL9 Promotes Chemoresistance of Pancreatic Ductal Adenocarcinoma via the AVL9-IκBα-SKP1 Complex\",\"authors\":\"Jinsheng Ding , Yongjie Xie , Ziyun Liu , Zhaoyu Zhang , Bo Ni , Jingrui Yan , Tianxing Zhou , Jihui Hao\",\"doi\":\"10.1053/j.gastro.2024.10.042\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background & Aims</h3><div>Gemcitabine combined with albumin-paclitaxel (AG) is a crucial therapeutic option for pancreatic ductal adenocarcinoma (PDAC). However, the response to chemotherapy is relatively poor, with rapid development of resistance. The aim of this study was to explore the mechanism of resistance to AG and to develop strategies that can sensitize the AG regimen.</div></div><div><h3>Methods</h3><div>We used organoid models, patient-derived xenografts, and genetically engineered mouse models in our study. Chromatin immunoprecipitation, double luciferase assay, co-immunoprecipitation, and far-western blotting analysis were performed to investigate the mechanism. The AVL9 inhibitors were identified through protein structure analysis and molecular docking analysis, and their efficacy was verified in patient-derived xenografts, patient-derived organoids-based xenograft, and KPC models.</div></div><div><h3>Results</h3><div>Through multistrategy screening, we identified AVL9 as a key target for AG resistance in PDAC. Its tumor-promoting effects were confirmed in our clinical cohorts. Mechanistically, HIF-1α, a hypoxia-related transcription factor, drives the expression of AVL9. AVL9 acts as a scaffold that facilitates the binding of IκBα to SKP1, leading to enhanced ubiquitination and degradation of IκBα, which further activates the nuclear factor–κB pathway. The potential AVL9-targeting inhibitor, Edotecarin, was shown to reverse AG chemo-resistance in PDAC.</div></div><div><h3>Conclusion</h3><div>AVL9 expression is driven by HIF-1α in PDAC. The physical interaction of AVL9, IκBα, and SKP1 provides a novel molecular mechanism for the abnormal activation of the nuclear factor–κB pathway. Therefore, the AVL9-targeting drug Edotecarin could be a promising therapeutic strategy for sensitizing PDAC to AG.</div></div>\",\"PeriodicalId\":12590,\"journal\":{\"name\":\"Gastroenterology\",\"volume\":\"168 3\",\"pages\":\"Pages 539-555.e5\"},\"PeriodicalIF\":25.7000,\"publicationDate\":\"2024-11-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Gastroenterology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0016508524056956\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Gastroenterology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0016508524056956","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
Hypoxic and Acidic Tumor Microenvironment–Driven AVL9 Promotes Chemoresistance of Pancreatic Ductal Adenocarcinoma via the AVL9-IκBα-SKP1 Complex
Background & Aims
Gemcitabine combined with albumin-paclitaxel (AG) is a crucial therapeutic option for pancreatic ductal adenocarcinoma (PDAC). However, the response to chemotherapy is relatively poor, with rapid development of resistance. The aim of this study was to explore the mechanism of resistance to AG and to develop strategies that can sensitize the AG regimen.
Methods
We used organoid models, patient-derived xenografts, and genetically engineered mouse models in our study. Chromatin immunoprecipitation, double luciferase assay, co-immunoprecipitation, and far-western blotting analysis were performed to investigate the mechanism. The AVL9 inhibitors were identified through protein structure analysis and molecular docking analysis, and their efficacy was verified in patient-derived xenografts, patient-derived organoids-based xenograft, and KPC models.
Results
Through multistrategy screening, we identified AVL9 as a key target for AG resistance in PDAC. Its tumor-promoting effects were confirmed in our clinical cohorts. Mechanistically, HIF-1α, a hypoxia-related transcription factor, drives the expression of AVL9. AVL9 acts as a scaffold that facilitates the binding of IκBα to SKP1, leading to enhanced ubiquitination and degradation of IκBα, which further activates the nuclear factor–κB pathway. The potential AVL9-targeting inhibitor, Edotecarin, was shown to reverse AG chemo-resistance in PDAC.
Conclusion
AVL9 expression is driven by HIF-1α in PDAC. The physical interaction of AVL9, IκBα, and SKP1 provides a novel molecular mechanism for the abnormal activation of the nuclear factor–κB pathway. Therefore, the AVL9-targeting drug Edotecarin could be a promising therapeutic strategy for sensitizing PDAC to AG.
期刊介绍:
Gastroenterology is the most prominent journal in the field of gastrointestinal disease. It is the flagship journal of the American Gastroenterological Association and delivers authoritative coverage of clinical, translational, and basic studies of all aspects of the digestive system, including the liver and pancreas, as well as nutrition.
Some regular features of Gastroenterology include original research studies by leading authorities, comprehensive reviews and perspectives on important topics in adult and pediatric gastroenterology and hepatology. The journal also includes features such as editorials, correspondence, and commentaries, as well as special sections like "Mentoring, Education and Training Corner," "Diversity, Equity and Inclusion in GI," "Gastro Digest," "Gastro Curbside Consult," and "Gastro Grand Rounds."
Gastroenterology also provides digital media materials such as videos and "GI Rapid Reel" animations. It is abstracted and indexed in various databases including Scopus, Biological Abstracts, Current Contents, Embase, Nutrition Abstracts, Chemical Abstracts, Current Awareness in Biological Sciences, PubMed/Medline, and the Science Citation Index.