Inhibition of STAT3-ferroptosis negative regulatory axis suppresses tumor growth and alleviates chemoresistance in gastric cancer.
Inhibition of STAT3-ferroptosis negative regulatory axis suppresses tumor growth and alleviates chemoresistance in gastric cancer.
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DOI：
10.1016/j.redox.2022.102317
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发表时间：
2022-06
期刊：
影响因子：
11.4
通讯作者：
Zhang, Xiaolei
中科院分区：
文献类型：
--
作者：
Ouyang, Shumin;Li, Huaxuan;Lou, Linlin;Huang, Qiuyao;Zhang, Zhenhua;Mo, Jianshan;Li, Min;Lu, Jiaye;Zhu, Kai;Chu, Yunjie;Ding, Wen;Zhu, Jianzheng;Lin, Ziyou;Zhong, Lin;Wang, Junjian;Yue, Peibin;Turkson, James;Liu, Peiqing;Wang, Yuanxiang;Zhang, Xiaolei
化疗仍是胃癌的主要治疗方法之一，但5-FU的临床应用因耐药而受到限制。在这里，我们证明了由STAT3抑制引起的铁性下垂可能为探索治疗胃癌和化疗耐药的新的有效治疗策略提供了一个新的机会。我们发现铁下垂负调控(FNR)信号与胃癌的进展和化疗耐药密切相关。FNR相关基因(Gpx4、SLC7A11和FTH1)和STAT3在5-FU耐药细胞和异种移植瘤中上调。进一步的证据表明，STAT3与FNR相关基因(Gpx4、SLC7A11和FTH1)启动子中一致的DNA反应元件结合并调节它们的表达，从而在胃癌中建立了一个负的STAT3铁下垂调控轴。STAT3活性的遗传抑制通过脂质过氧化和Fe2+在胃癌细胞中的积累触发铁下垂。我们进一步开发了一种有效和选择性的STAT3抑制剂W1131，它在胃癌细胞异种移植模型、有机化合物模型和患者来源的异种移植(PDX)模型中显示出显著的抗肿瘤作用，部分是通过诱导铁下垂来实现的，从而为晚期胃癌提供了一种新的候选化合物。此外，靶向STAT3-铁性下垂通路可促进铁性下垂并恢复对化疗的敏感性。我们的研究结果表明，STAT3是胃癌中铁下垂的关键负性调节因子，是一种多管齐下的机制，为晚期胃癌和化疗耐药提供了一种新的治疗策略。靶向STAT3-铁下垂通路为晚期胃癌和化疗耐药提供了新的治疗策略。STAT3的基因抑制通过下调SLC7A11、Gpx4和FTH1的表达，触发铁性上睑下垂的铁依赖性氧化损伤。新型STAT3抑制剂W1131通过诱导铁下垂抑制胃癌进展并减轻化疗耐药。STAT3的基因和药物抑制通过转录调控Gpx4、SLC7A11和FTH1在胃癌中触发铁下垂。开发了一种高效、选择性的STAT3抑制剂W1131，具有很强的抗肿瘤作用。铁下垂在胃癌的进展和化疗耐药中起关键作用。靶向STAT3-铁下垂通路为晚期胃癌和化疗耐药提供了新的治疗策略。
Chemotherapy is still one of the principal treatments for gastric cancer, but the clinical application of 5-FU is limited by drug resistance. Here, we demonstrate that ferroptosis triggered by STAT3 inhibition may provide a novel opportunity to explore a new effective therapeutic strategy for gastric cancer and chemotherapy resistance. We find that ferroptosis negative regulation (FNR) signatures are closely correlated with the progression and chemoresistance of gastric cancer. FNR associated genes (GPX4, SLC7A11, and FTH1) and STAT3 are upregulated in 5-FU resistant cells and xenografts. Further evidence demonstrates that STAT3 binds to consensus DNA response elements in the promoters of the FNR associated genes (GPX4, SLC7A11, and FTH1) and regulates their expression, thereby establishing a negative STAT3-ferroptosis regulatory axis in gastric cancer. Genetic inhibition of STAT3 activity triggers ferroptosis through lipid peroxidation and Fe2+ accumulation in gastric cancer cells. We further develop a potent and selective STAT3 inhibitor, W1131, which demonstrates significant anti-tumor effects in gastric cancer cell xenograft model, organoids model, and patient-derived xenografts (PDX) model partly by inducing ferroptosis, thus providing a new candidate compound for advanced gastric cancer. Moreover, targeting the STAT3-ferroptosis circuit promotes ferroptosis and restores sensitivity to chemotherapy. Our finding reveals that STAT3 acts as a key negative regulator of ferroptosis in gastric cancer through a multi-pronged mechanism and provides a new therapeutic strategy for advanced gastric cancer and chemotherapy resistance. Targeting the STAT3-ferroptosis circuit provides a new therapeutic strategy for advanced gastric cancer and chemotherapy resistance. Genetic inhibition of STAT3 triggers iron-dependent oxidative damage of ferroptosis through down-regulation of SLC7A11, GPX4, and FTH1. Novel STAT3 inhibitor W1131 suppresses gastric cancer progression and alleviates chemoresistance partly by induction of ferroptosis. Genetic and pharmacological inhibition of STAT3 triggers ferroptosis by transcriptionlly regulation of GPX4, SLC7A11, and FTH1 in gastric cancer. A potent and selective STAT3 inhibitor W1131, with strong anti-tumor effects, is developed. Ferroptosis plays a key role in the progression and chemoresistance of gastric cancer. Targeting the STAT3-ferroptosis circuit provides a new therapeutic strategy for advanced gastric cancer and chemotherapy resistance.
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ACSL4 通过塑造细胞脂质成分来决定铁死亡敏感性。
影响因子：
14.8
作者：
Doll S;Proneth B;Tyurina YY;Panzilius E;Kobayashi S;Ingold I;Irmler M;Beckers J;Aichler M;Walch A;Prokisch H;Trümbach D;Mao G;Qu F;Bayir H;Füllekrug J;Scheel CH;Wurst W;Schick JA;Kagan VE;Angeli JP;Conrad M
通讯作者：
Conrad M
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
5.5
作者：
Chen X;Yu C;Kang R;Tang D
通讯作者：
Tang D
影响因子：
29.4
作者：
Judd, Louise M.;Bredin, Karin;Giraud, Andrew S.
通讯作者：
Giraud, Andrew S.
影响因子：
11.2
作者：
Hussain, S. Farzana;Kong, Ling-Yuan;Heimberger, Amy B.
通讯作者：
Heimberger, Amy B.