Barbara Del Bello , Cristina Ulivieri , Emilia Maellaro
{"title":"Hypoxia response in glioblastoma cells: effect of trehalose on macropinocytosis, autophagy and cell survival","authors":"Barbara Del Bello , Cristina Ulivieri , Emilia Maellaro","doi":"10.1016/j.bbrep.2025.102284","DOIUrl":null,"url":null,"abstract":"<div><div>In glioblastoma multiforme, the most malignant brain tumor in adults, the hypoxic milieu is believed to contribute to tumor aggressiveness and resistance to therapy. Here, human glioblastoma U373-MG and T98G cells were exposed to hypoxia (1 % oxygen) or normoxia (18 % oxygen), and treated with trehalose, a natural disaccharide increasingly studied for its therapeutic potential in cancer. In all samples under hypoxia, HIF-1α stabilization was accompanied by a decrease in Nrf2 and p62/SQSTM1 proteins; redox imbalance also occurred, as documented by increased levels of ROS and parallel lowering of glutathione. Trehalose treatment increased Nrf2 and p62 proteins under normoxia, an effect lost or downsized under hypoxia. Differently, under both oxygen concentrations, trehalose increased glutathione content, consistently with its antioxidant role. In U373-MG cells, trehalose induced remarkable macropinocytosis under hypoxia, albeit less than under normoxia; on the contrary, in autophagy-proficient T98G cells, trehalose further increased the autophagic process under hypoxia compared to normoxia. As regards long-term cell fate (evaluated as colony-forming capacity), hypoxia only proved to be a favorable condition for T98G cells. However, in both cell lines, trehalose treatment significantly and dose-dependently decreased clonogenic capacity under normoxia and hypoxia; in particular, the long-lasting stimulation of macropinocytosis in U373-MG cells induced extensive cell death by methuosis. Overall, our findings suggest that trehalose-induced macropinocytosis or autophagy could also play a tumour-suppressive role in the hypoxic tumor milieu that characterizes glioblastoma, making its synergy with conventional chemotherapy and radiotherapy worth exploring.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"44 ","pages":"Article 102284"},"PeriodicalIF":2.2000,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochemistry and Biophysics Reports","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2405580825003711","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
In glioblastoma multiforme, the most malignant brain tumor in adults, the hypoxic milieu is believed to contribute to tumor aggressiveness and resistance to therapy. Here, human glioblastoma U373-MG and T98G cells were exposed to hypoxia (1 % oxygen) or normoxia (18 % oxygen), and treated with trehalose, a natural disaccharide increasingly studied for its therapeutic potential in cancer. In all samples under hypoxia, HIF-1α stabilization was accompanied by a decrease in Nrf2 and p62/SQSTM1 proteins; redox imbalance also occurred, as documented by increased levels of ROS and parallel lowering of glutathione. Trehalose treatment increased Nrf2 and p62 proteins under normoxia, an effect lost or downsized under hypoxia. Differently, under both oxygen concentrations, trehalose increased glutathione content, consistently with its antioxidant role. In U373-MG cells, trehalose induced remarkable macropinocytosis under hypoxia, albeit less than under normoxia; on the contrary, in autophagy-proficient T98G cells, trehalose further increased the autophagic process under hypoxia compared to normoxia. As regards long-term cell fate (evaluated as colony-forming capacity), hypoxia only proved to be a favorable condition for T98G cells. However, in both cell lines, trehalose treatment significantly and dose-dependently decreased clonogenic capacity under normoxia and hypoxia; in particular, the long-lasting stimulation of macropinocytosis in U373-MG cells induced extensive cell death by methuosis. Overall, our findings suggest that trehalose-induced macropinocytosis or autophagy could also play a tumour-suppressive role in the hypoxic tumor milieu that characterizes glioblastoma, making its synergy with conventional chemotherapy and radiotherapy worth exploring.
期刊介绍:
Open access, online only, peer-reviewed international journal in the Life Sciences, established in 2014 Biochemistry and Biophysics Reports (BB Reports) publishes original research in all aspects of Biochemistry, Biophysics and related areas like Molecular and Cell Biology. BB Reports welcomes solid though more preliminary, descriptive and small scale results if they have the potential to stimulate and/or contribute to future research, leading to new insights or hypothesis. Primary criteria for acceptance is that the work is original, scientifically and technically sound and provides valuable knowledge to life sciences research. We strongly believe all results deserve to be published and documented for the advancement of science. BB Reports specifically appreciates receiving reports on: Negative results, Replication studies, Reanalysis of previous datasets.