靶向 MGST1 通过表观遗传学增强 ALOX15 介导的铁突变,使非小细胞肺癌细胞对放疗敏感

IF 2.3 4区 医学 Q3 ONCOLOGY
Yechen Ma, Yuping Peng, Shulin Cheng, Long Jin
{"title":"靶向 MGST1 通过表观遗传学增强 ALOX15 介导的铁突变,使非小细胞肺癌细胞对放疗敏感","authors":"Yechen Ma, Yuping Peng, Shulin Cheng, Long Jin","doi":"10.2174/0115680096317925240820053934","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Ferroptosis is closely related to radiotherapy resistance in multiple can-cers. Herein, the role of microsomal glutathione S-transferase 1 (MGST1) in regulating ferropto-sis and radiotherapy resistance in non-small cell lung cancer (NSCLC) was investigated.</p><p><strong>Methods: </strong>Radiation-resistant NSCLC cells (NCI-1299-IR and HCC827-IR cells) were estab-lished. After exposure to X-ray, cell proliferation and survival were assessed by colony formation assay and CCK-8 assay, and lipid ROS level was examined by the fluorophore BODIPY™ 581/591 C11. MDA, GSH, and Fe2+ levels were measured by ELISA kits. The molecular interac-tion was analyzed using ChIP and MSP assays.</p><p><strong>Results: </strong>Our results showed that RSL3 treatment greatly enhanced the radiotherapy sensitivity of NCI-1299-IR and HCC827-IR cells. It was subsequently revealed that MGST1 was highly ex-pressed in NCI-1299-IR and HCC827-IR cells than its parent cells, and silencing of MGST1 re-duced radioresistance of NCI-1299-IR and HCC827-IR cells by facilitating ferroptosis. Mechanis-tically, MGST1 knockdown greatly reduced HO-1 and DNMT1/3A protein levels, leading to re-duced DNA methylation on the ALOX15 promoter region, thereby epigenetically upregulating ALOX15 expression. As expected, the promoting effects of MGST1 silencing on radiosensitivity and ferroptosis in radiation-resistant NSCLC cells were strikingly eliminated by ALOX15 knock-down.</p><p><strong>Conclusion: </strong>MGST1 knockdown epigenetically enhanced radiotherapy sensitivity of NCSLC cells by promoting ALOX15-mediated ferroptosis through regulating the HO-1/DNMT1 pathway.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":" ","pages":""},"PeriodicalIF":2.3000,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Targeting MGST1 Makes Non-Small Cell Lung Cancer Cells Sensitive to Radiotherapy by Epigenetically Enhancing ALOX15-Mediated Ferroptosis.\",\"authors\":\"Yechen Ma, Yuping Peng, Shulin Cheng, Long Jin\",\"doi\":\"10.2174/0115680096317925240820053934\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Ferroptosis is closely related to radiotherapy resistance in multiple can-cers. Herein, the role of microsomal glutathione S-transferase 1 (MGST1) in regulating ferropto-sis and radiotherapy resistance in non-small cell lung cancer (NSCLC) was investigated.</p><p><strong>Methods: </strong>Radiation-resistant NSCLC cells (NCI-1299-IR and HCC827-IR cells) were estab-lished. After exposure to X-ray, cell proliferation and survival were assessed by colony formation assay and CCK-8 assay, and lipid ROS level was examined by the fluorophore BODIPY™ 581/591 C11. MDA, GSH, and Fe2+ levels were measured by ELISA kits. The molecular interac-tion was analyzed using ChIP and MSP assays.</p><p><strong>Results: </strong>Our results showed that RSL3 treatment greatly enhanced the radiotherapy sensitivity of NCI-1299-IR and HCC827-IR cells. It was subsequently revealed that MGST1 was highly ex-pressed in NCI-1299-IR and HCC827-IR cells than its parent cells, and silencing of MGST1 re-duced radioresistance of NCI-1299-IR and HCC827-IR cells by facilitating ferroptosis. Mechanis-tically, MGST1 knockdown greatly reduced HO-1 and DNMT1/3A protein levels, leading to re-duced DNA methylation on the ALOX15 promoter region, thereby epigenetically upregulating ALOX15 expression. As expected, the promoting effects of MGST1 silencing on radiosensitivity and ferroptosis in radiation-resistant NSCLC cells were strikingly eliminated by ALOX15 knock-down.</p><p><strong>Conclusion: </strong>MGST1 knockdown epigenetically enhanced radiotherapy sensitivity of NCSLC cells by promoting ALOX15-mediated ferroptosis through regulating the HO-1/DNMT1 pathway.</p>\",\"PeriodicalId\":10816,\"journal\":{\"name\":\"Current cancer drug targets\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":2.3000,\"publicationDate\":\"2024-09-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Current cancer drug targets\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2174/0115680096317925240820053934\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current cancer drug targets","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2174/0115680096317925240820053934","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

背景:铁蛋白沉积与多种癌症的放疗耐药性密切相关。本文研究了微粒体谷胱甘肽 S 转移酶 1(MGST1)在非小细胞肺癌(NSCLC)中调控铁蛋白沉积和放疗耐药性的作用:方法:建立抗放射治疗的NSCLC细胞(NCI-1299-IR和HCC827-IR细胞)。暴露于 X 射线后,细胞增殖和存活通过集落形成试验和 CCK-8 试验进行评估,脂质 ROS 水平通过荧光团 BODIPY™ 581/591 C11 进行检测。MDA、GSH 和 Fe2+ 含量通过 ELISA 试剂盒进行测定。使用 ChIP 和 MSP 检测分析了分子间的相互作用:结果:我们的研究结果表明,RSL3能大大提高NCI-1299-IR和HCC827-IR细胞的放疗敏感性。随后的研究发现,MGST1在NCI-1299-IR和HCC827-IR细胞中的外显率高于其母细胞,而沉默MGST1可通过促进铁凋亡重新降低NCI-1299-IR和HCC827-IR细胞的放射抗性。从机理上讲,MGST1的敲除大大降低了HO-1和DNMT1/3A蛋白的水平,导致ALOX15启动子区域的DNA甲基化重新降低,从而在表观遗传学上上调了ALOX15的表达。正如预期的那样,MGST1沉默对耐辐射NSCLC细胞放射敏感性和铁变态反应的促进作用被ALOX15敲除所显著消除:结论:MGST1基因敲除通过调控HO-1/DNMT1通路促进ALOX15介导的铁蜕变,从而从表观遗传学角度提高了NSCLC细胞的放疗敏感性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeting MGST1 Makes Non-Small Cell Lung Cancer Cells Sensitive to Radiotherapy by Epigenetically Enhancing ALOX15-Mediated Ferroptosis.

Background: Ferroptosis is closely related to radiotherapy resistance in multiple can-cers. Herein, the role of microsomal glutathione S-transferase 1 (MGST1) in regulating ferropto-sis and radiotherapy resistance in non-small cell lung cancer (NSCLC) was investigated.

Methods: Radiation-resistant NSCLC cells (NCI-1299-IR and HCC827-IR cells) were estab-lished. After exposure to X-ray, cell proliferation and survival were assessed by colony formation assay and CCK-8 assay, and lipid ROS level was examined by the fluorophore BODIPY™ 581/591 C11. MDA, GSH, and Fe2+ levels were measured by ELISA kits. The molecular interac-tion was analyzed using ChIP and MSP assays.

Results: Our results showed that RSL3 treatment greatly enhanced the radiotherapy sensitivity of NCI-1299-IR and HCC827-IR cells. It was subsequently revealed that MGST1 was highly ex-pressed in NCI-1299-IR and HCC827-IR cells than its parent cells, and silencing of MGST1 re-duced radioresistance of NCI-1299-IR and HCC827-IR cells by facilitating ferroptosis. Mechanis-tically, MGST1 knockdown greatly reduced HO-1 and DNMT1/3A protein levels, leading to re-duced DNA methylation on the ALOX15 promoter region, thereby epigenetically upregulating ALOX15 expression. As expected, the promoting effects of MGST1 silencing on radiosensitivity and ferroptosis in radiation-resistant NSCLC cells were strikingly eliminated by ALOX15 knock-down.

Conclusion: MGST1 knockdown epigenetically enhanced radiotherapy sensitivity of NCSLC cells by promoting ALOX15-mediated ferroptosis through regulating the HO-1/DNMT1 pathway.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Current cancer drug targets
Current cancer drug targets 医学-肿瘤学
CiteScore
5.40
自引率
0.00%
发文量
105
审稿时长
1 months
期刊介绍: Current Cancer Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular drug targets involved in cancer, e.g. disease specific proteins, receptors, enzymes and genes. Current Cancer Drug Targets publishes original research articles, letters, reviews / mini-reviews, drug clinical trial studies and guest edited thematic issues written by leaders in the field covering a range of current topics on drug targets involved in cancer. As the discovery, identification, characterization and validation of novel human drug targets for anti-cancer drug discovery continues to grow; this journal has become essential reading for all pharmaceutical scientists involved in drug discovery and development.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信