{"title":"丹参酮I通过KDM4D/p53通路诱导胃癌细胞铁下垂。","authors":"Minming Xia, Yifeng Wu, Hui Zhu, Wenbiao Duan","doi":"10.1177/09603271231216963","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Tanshinone I (Tan I) is one of the bioactive components of <i>Salvia miltiorrhiza</i>. Whether it inhibits gastric cancer through ferroptosis has not been reported. This study aimed to confirm the effect of Tan I on ferroptosis in gastric cancer cells.</p><p><strong>Methods: </strong>AGS and HGC27 cells were treated with Tan I. First, oxidative stress-related parameters and the expression of ferroptosis-related proteins were examined. Combined with a ferroptosis inhibitor, Tan I was found to inhibit gastric cancer cells via the ferroptosis pathway. Finally, with bioinformatics analysis, the target protein of Tan I was identified.</p><p><strong>Results: </strong>Tan I significantly inhibited the expression level of GPX4. This molecule also increased ROS, MDA, and Fe<sup>2+</sup> contents and decreased GSH enzyme activity. Therefore, we hypothesized that Tan I may inhibit gastric cancer cells by inducing ferroptosis. Western blotting results showed that Tan I inhibited the expression levels of the ferroptosis resistance-related proteins GPX4, SLC7A11, and FTH1, while the pro-ferroptosis-related proteins TFR1 and ACSL4 were significantly upregulated. A ferroptosis inhibitor effectively reversed these regulatory effects of Tan I in gastric cancer. With these data combined with the bioinformatics analysis, KDM4D was identified as a key regulatory target of Tan I. Mechanistically, Tan I induced positive regulation of ferroptosis resistance-related indicators by inhibiting KDM4D to upregulate p53 protein expression. Overexpression of KDM4D significantly reversed the effect of Tan I-induced ferroptosis resistance in gastric cancer cells.</p><p><strong>Conclusions: </strong>Tan I induced ferroptosis inhibition in gastric cancer by regulating the KDM4D/p53 pathway.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Tanshinone I induces ferroptosis in gastric cancer cells via the KDM4D/p53 pathway.\",\"authors\":\"Minming Xia, Yifeng Wu, Hui Zhu, Wenbiao Duan\",\"doi\":\"10.1177/09603271231216963\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>Tanshinone I (Tan I) is one of the bioactive components of <i>Salvia miltiorrhiza</i>. Whether it inhibits gastric cancer through ferroptosis has not been reported. This study aimed to confirm the effect of Tan I on ferroptosis in gastric cancer cells.</p><p><strong>Methods: </strong>AGS and HGC27 cells were treated with Tan I. First, oxidative stress-related parameters and the expression of ferroptosis-related proteins were examined. Combined with a ferroptosis inhibitor, Tan I was found to inhibit gastric cancer cells via the ferroptosis pathway. Finally, with bioinformatics analysis, the target protein of Tan I was identified.</p><p><strong>Results: </strong>Tan I significantly inhibited the expression level of GPX4. This molecule also increased ROS, MDA, and Fe<sup>2+</sup> contents and decreased GSH enzyme activity. Therefore, we hypothesized that Tan I may inhibit gastric cancer cells by inducing ferroptosis. Western blotting results showed that Tan I inhibited the expression levels of the ferroptosis resistance-related proteins GPX4, SLC7A11, and FTH1, while the pro-ferroptosis-related proteins TFR1 and ACSL4 were significantly upregulated. A ferroptosis inhibitor effectively reversed these regulatory effects of Tan I in gastric cancer. With these data combined with the bioinformatics analysis, KDM4D was identified as a key regulatory target of Tan I. Mechanistically, Tan I induced positive regulation of ferroptosis resistance-related indicators by inhibiting KDM4D to upregulate p53 protein expression. Overexpression of KDM4D significantly reversed the effect of Tan I-induced ferroptosis resistance in gastric cancer cells.</p><p><strong>Conclusions: </strong>Tan I induced ferroptosis inhibition in gastric cancer by regulating the KDM4D/p53 pathway.</p>\",\"PeriodicalId\":94029,\"journal\":{\"name\":\"Human & experimental toxicology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"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\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1177/09603271231216963\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Human & experimental toxicology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1177/09603271231216963","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
摘要
简介:丹参酮I (Tanshinone I, Tan I)是丹参的生物活性成分之一。是否通过铁下垂抑制胃癌尚未见报道。本研究旨在证实Tan I对胃癌细胞铁下垂的影响。方法:用Tan i处理AGS和HGC27细胞，首先检测氧化应激相关参数和凋亡相关蛋白的表达。与铁下垂抑制剂联合，发现Tan I通过铁下垂途径抑制胃癌细胞。最后，通过生物信息学分析，鉴定了Tan I的靶蛋白。结果:Tan I显著抑制GPX4的表达水平。该分子还增加了ROS、MDA和Fe2+含量，降低了GSH酶活性。因此，我们假设Tan I可能通过诱导铁下垂来抑制胃癌细胞。Western blotting结果显示，Tan I抑制了铁沉耐药相关蛋白GPX4、SLC7A11和FTH1的表达水平，而促铁沉相关蛋白TFR1和ACSL4的表达水平显著上调。一种铁下垂抑制剂有效地逆转了Tan I在胃癌中的这些调节作用。结合这些数据和生物信息学分析，我们确定KDM4D是Tan I的一个关键调控靶点，在机制上，Tan I通过抑制KDM4D上调p53蛋白表达，诱导铁下沉抗性相关指标的正向调节。过表达KDM4D可显著逆转Tan i诱导的胃癌细胞铁下垂抵抗作用。结论:Tan I通过调节KDM4D/p53通路诱导胃癌铁下垂抑制。
Tanshinone I induces ferroptosis in gastric cancer cells via the KDM4D/p53 pathway.
Introduction: Tanshinone I (Tan I) is one of the bioactive components of Salvia miltiorrhiza. Whether it inhibits gastric cancer through ferroptosis has not been reported. This study aimed to confirm the effect of Tan I on ferroptosis in gastric cancer cells.
Methods: AGS and HGC27 cells were treated with Tan I. First, oxidative stress-related parameters and the expression of ferroptosis-related proteins were examined. Combined with a ferroptosis inhibitor, Tan I was found to inhibit gastric cancer cells via the ferroptosis pathway. Finally, with bioinformatics analysis, the target protein of Tan I was identified.
Results: Tan I significantly inhibited the expression level of GPX4. This molecule also increased ROS, MDA, and Fe2+ contents and decreased GSH enzyme activity. Therefore, we hypothesized that Tan I may inhibit gastric cancer cells by inducing ferroptosis. Western blotting results showed that Tan I inhibited the expression levels of the ferroptosis resistance-related proteins GPX4, SLC7A11, and FTH1, while the pro-ferroptosis-related proteins TFR1 and ACSL4 were significantly upregulated. A ferroptosis inhibitor effectively reversed these regulatory effects of Tan I in gastric cancer. With these data combined with the bioinformatics analysis, KDM4D was identified as a key regulatory target of Tan I. Mechanistically, Tan I induced positive regulation of ferroptosis resistance-related indicators by inhibiting KDM4D to upregulate p53 protein expression. Overexpression of KDM4D significantly reversed the effect of Tan I-induced ferroptosis resistance in gastric cancer cells.
Conclusions: Tan I induced ferroptosis inhibition in gastric cancer by regulating the KDM4D/p53 pathway.
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