Targeting NRF2 Sensitizes Esophageal Adenocarcinoma Cells to Cisplatin through Induction of Ferroptosis and Apoptosis.
Targeting NRF2 Sensitizes Esophageal Adenocarcinoma Cells to Cisplatin through Induction of Ferroptosis and Apoptosis.
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DOI：
10.3390/antiox11101859
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发表时间：
2022-09-21
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--
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食管腺癌（EAC）是美国食管癌的主要类型，通过Barrett食管（BE）-异型增生-癌级联发展。胃食管反流病，即酸性胆汁盐反流进入食管，是BE发展及其进展为EAC的主要风险因素。NFE 2相关因子2（NRF 2）是主要的细胞抗氧化调节剂。我们在EAC细胞系和原代组织中检测到高的NRF 2蛋白水平。敲低NRF 2显著增强酸性胆盐诱导的氧化应激、DNA损伤，并抑制EAC细胞生长。NRF 2抑制剂阿糖胞苷显著抑制NRF 2转录活性并下调NRF 2靶基因。我们发现，除了诱导细胞凋亡，单独或与顺铂（CDDP）联合使用的曲马多还诱导了显著的脂质过氧化和铁凋亡，如两种已知的铁凋亡标志物xCT和GPX 4表达减少所证明的。阿曲唑和CDDP的组合在体内显著抑制EAC肿瘤异种移植物生长，并证实了体外数据，其显示铁凋亡是用阿曲唑或阿曲唑和CDDP组合治疗的肿瘤中的重要机制。我们的数据支持NRF 2在保护EAC免受应激诱导的细胞凋亡和铁凋亡中的作用。靶向NRF 2联合铂类治疗可能是消除EAC中癌细胞的有效策略。
Esophageal adenocarcinoma (EAC), the predominant type of esophageal cancer in the United States, develops through Barrett’s esophagus (BE)-dysplasia-carcinoma cascade. Gastroesophageal reflux disease, where acidic bile salts refluxate into the esophagus, is the main risk factor for the development of BE and its progression to EAC. The NFE2-related factor 2 (NRF2) is the master cellular antioxidant regulator. We detected high NRF2 protein levels in the EAC cell lines and primary tissues. Knockdown of NRF2 significantly enhanced acidic bile salt-induced oxidative stress, DNA damage, and inhibited EAC cell growth. Brusatol, an NRF2 inhibitor, significantly inhibited NRF2 transcriptional activity and downregulated the NRF2 target genes. We discovered that in addition to inducing apoptosis, Brusatol alone or in combination with cisplatin (CDDP) induced significant lipid peroxidation and ferroptosis, as evidenced by reduced xCT and GPX4 expression, two known ferroptosis markers. The combination of Brusatol and CDDP significantly inhibited EAC tumor xenograft growth in vivo and confirmed the in vitro data showing ferroptosis as an important mechanism in the tumors treated with Brusatol or Brusatol and CDDP combination. Our data support the role of NRF2 in protecting against stress-induced apoptosis and ferroptosis in EACs. Targeting NRF2 in combination with platinum therapy can be an effective strategy for eliminating cancer cells in EAC.
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