{"title":"Hypoxia-elicited exosomal HIF-1α promotes drug resistance of melanoma through modulating SLC7A11 ubiquitination","authors":"Jiaoquan Chen, Hui Zou, Bihua Liang, Yeqing Gong, Shaoyin Ma, Runxiang Li, Jiacong Zeng, Chao Bi, Huilan Zhu","doi":"10.1016/j.cellsig.2025.111939","DOIUrl":null,"url":null,"abstract":"<div><div>Drug resistance poses a significant challenge in the clinical management of melanoma, primarily driven by the hypoxic tumor microenvironment. This study aims to elucidate the molecular mechanisms underlying drug resistance in melanoma under hypoxic conditions. Exosomes were isolated from melanoma cells cultured under normoxic (Nor-exos) and hypoxic (Hypo-exos) environments. The proliferative capacity of tumor cells was assessed using CCK-8 and colony formation assays, while relevant molecular expressions were evaluated through qPCR, Western blotting, immunofluorescence, and immunohistochemistry. Additionally, mitochondrial damage was examined via transmission electron microscopy, and reactive oxygen species (ROS) levels were quantified using flow cytometry. Xenograft models further facilitated the investigation into the molecular mechanisms of drug resistance. Hypo-exos promote drug resistance in melanoma cells by inhibiting ferroptosis; mechanistically, Hypo-exos inhibiting p53 and OTUB1 expression through HIF-1α transfer. Furthermore, OTUB1 enhances SLC7A11 stability, thereby reducing ferroptosis levels and fostering drug resistance in melanoma. Our findings indicate that Hypo-exos inhibit ferroptosis to augment drug resistance in melanoma by delivering HIF-1α to modulate the p53/OTUB1/SLC7A11 axis. Exosomal HIF-1α may represent a promising biomarker and therapeutic target for addressing drug resistance in melanoma.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"134 ","pages":"Article 111939"},"PeriodicalIF":3.7000,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cellular signalling","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0898656825003547","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Drug resistance poses a significant challenge in the clinical management of melanoma, primarily driven by the hypoxic tumor microenvironment. This study aims to elucidate the molecular mechanisms underlying drug resistance in melanoma under hypoxic conditions. Exosomes were isolated from melanoma cells cultured under normoxic (Nor-exos) and hypoxic (Hypo-exos) environments. The proliferative capacity of tumor cells was assessed using CCK-8 and colony formation assays, while relevant molecular expressions were evaluated through qPCR, Western blotting, immunofluorescence, and immunohistochemistry. Additionally, mitochondrial damage was examined via transmission electron microscopy, and reactive oxygen species (ROS) levels were quantified using flow cytometry. Xenograft models further facilitated the investigation into the molecular mechanisms of drug resistance. Hypo-exos promote drug resistance in melanoma cells by inhibiting ferroptosis; mechanistically, Hypo-exos inhibiting p53 and OTUB1 expression through HIF-1α transfer. Furthermore, OTUB1 enhances SLC7A11 stability, thereby reducing ferroptosis levels and fostering drug resistance in melanoma. Our findings indicate that Hypo-exos inhibit ferroptosis to augment drug resistance in melanoma by delivering HIF-1α to modulate the p53/OTUB1/SLC7A11 axis. Exosomal HIF-1α may represent a promising biomarker and therapeutic target for addressing drug resistance in melanoma.
期刊介绍:
Cellular Signalling publishes original research describing fundamental and clinical findings on the mechanisms, actions and structural components of cellular signalling systems in vitro and in vivo.
Cellular Signalling aims at full length research papers defining signalling systems ranging from microorganisms to cells, tissues and higher organisms.