{"title":"Microsomal glutathione S-transferase 1 targets the autophagy signaling pathway to suppress ferroptosis in gastric carcinoma cells.","authors":"Z Peng, N Peng","doi":"10.1177/09603271231172915","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>Ferroptosis is a newly discovered form of programmed cell death; however, the specific mechanisms that regulate ferroptosis have yet to be fully elucidated in gastric carcinoma. In this study, we aimed to investigate how microsomal glutathione S-transferase 1 (MGST1) regulates ferroptosis in gastric carcinoma cells.</p><p><strong>Methods: </strong>Gastric adenocarcinoma (SGC7901) cells that overexpressed MGST1 or expressed only low levels of MGST1, were treated with specific compounds (erastin, sorafenib, RSL3, MK-2206 and SC79). Then, we detected the levels of malondialdehyde (MDA), glutathione (GSH), iron and reactive oxygen species (ROS). Protein expression levels of the non-classical autophagy and protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) pathways were determined by western blotting and cell viability was analyzed by Cell Counting Kit-8 (CCK-8) assays. The expressions of target genes were detected using qRT-PCR.</p><p><strong>Results: </strong>We evaluated a range of ferroptosis-inducing compounds and found that MGST1 expression was down-regulated during ferroptosis in SGC7901 cells. The ferroptosis inducer RSL3 played a role in classical ferroptotic events while the overexpression of MGST1 impaired these effects. Interestingly, the overexpression of MGST1 resulted in the inactivation of autophagy by repressing the expression of ATG16L1 and the conversion of LC3-I to LC3-II. The upregulation of ATG16L1 eliminated the inhibitory action of MGST1 on ferroptosis. Notably, the overexpression of MGST1 induced the activation of the Akt/GSK-3β pathway. An Akt inhibitor antagonized the inhibitory effects of MGST1 on autophagy and ferroptosis.</p><p><strong>Conclusion: </strong>Collectively, our findings demonstrate a novel molecular mechanism and signaling pathway for ferroptosis. We also characterized that the overexpression of MGST1 induces gastric carcinoma cell proliferation by activating the Akt/GSK-3β signaling pathway.</p>","PeriodicalId":13181,"journal":{"name":"Human & Experimental Toxicology","volume":null,"pages":null},"PeriodicalIF":2.7000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Human & Experimental Toxicology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1177/09603271231172915","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"TOXICOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Objective: Ferroptosis is a newly discovered form of programmed cell death; however, the specific mechanisms that regulate ferroptosis have yet to be fully elucidated in gastric carcinoma. In this study, we aimed to investigate how microsomal glutathione S-transferase 1 (MGST1) regulates ferroptosis in gastric carcinoma cells.
Methods: Gastric adenocarcinoma (SGC7901) cells that overexpressed MGST1 or expressed only low levels of MGST1, were treated with specific compounds (erastin, sorafenib, RSL3, MK-2206 and SC79). Then, we detected the levels of malondialdehyde (MDA), glutathione (GSH), iron and reactive oxygen species (ROS). Protein expression levels of the non-classical autophagy and protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) pathways were determined by western blotting and cell viability was analyzed by Cell Counting Kit-8 (CCK-8) assays. The expressions of target genes were detected using qRT-PCR.
Results: We evaluated a range of ferroptosis-inducing compounds and found that MGST1 expression was down-regulated during ferroptosis in SGC7901 cells. The ferroptosis inducer RSL3 played a role in classical ferroptotic events while the overexpression of MGST1 impaired these effects. Interestingly, the overexpression of MGST1 resulted in the inactivation of autophagy by repressing the expression of ATG16L1 and the conversion of LC3-I to LC3-II. The upregulation of ATG16L1 eliminated the inhibitory action of MGST1 on ferroptosis. Notably, the overexpression of MGST1 induced the activation of the Akt/GSK-3β pathway. An Akt inhibitor antagonized the inhibitory effects of MGST1 on autophagy and ferroptosis.
Conclusion: Collectively, our findings demonstrate a novel molecular mechanism and signaling pathway for ferroptosis. We also characterized that the overexpression of MGST1 induces gastric carcinoma cell proliferation by activating the Akt/GSK-3β signaling pathway.
期刊介绍:
Human and Experimental Toxicology (HET), an international peer reviewed journal, is dedicated to publishing preclinical and clinical original research papers and in-depth reviews that comprehensively cover studies of functional, biochemical and structural disorders in toxicology. The principal aim of the HET is to publish timely high impact hypothesis driven scholarly work with an international scope. The journal publishes on: Structural, functional, biochemical, and molecular effects of toxic agents; Studies that address mechanisms/modes of toxicity; Safety evaluation of novel chemical, biotechnologically-derived products, and nanomaterials for human health assessment including statistical and mechanism-based approaches; Novel methods or approaches to research on animal and human tissues (medical and veterinary patients) investigating functional, biochemical and structural disorder; in vitro techniques, particularly those supporting alternative methods