阿司匹林通过限制NF-κBp65激活的SLC7A11转录来触发肝细胞癌细胞中的铁毒性
Aspirin triggers ferroptosis in hepatocellular carcinoma cells through restricting NF-κB p65-activated SLC7A11 transcription
影响因子:8.40000
分区:医学2区 / 药学1区 化学：综合2区
发表日期:2023 Aug
作者:
Yu-Fei Wang, Jin-Yan Feng, Li-Na Zhao, Man Zhao, Xian-Fu Wei, Yu Geng, Hong-Feng Yuan, Chun-Yu Hou, Hui-Hui Zhang, Guo-Wen Wang, Guang Yang, Xiao-Dong Zhang
摘要
许多研究表明，阿司匹林通常是处方药，可防止肝细胞癌（HCC）的发展。铁凋亡作为动态肿瘤抑制剂在肝癌发生中起着至关重要的作用。在这项研究中，我们研究了阿司匹林是否影响肝癌细胞中的铁凋亡。 RNA-seq分析表明，阿司匹林上调了4个与阿司匹林治疗的HEPG2细胞中的4个与氟凋亡相关的驱动因素，并下调了5个与螺栓毒相关的抑制剂。阿司匹林（4毫米）的治疗在HEPG2和HUH7细胞中诱导了明显的铁铁作用，这通过诱导蛋白的Erastin（10μM）增强了。我们证明了NF-κBp65通过直接与SLC7A11启动子的核心区域结合并激活抑制抑制剂SLC7A11的转录，而阿司匹林通过抑制NF-κBP65-P65-Activivectivecription诱导肥大，限制了HEPG2和HUH7细胞中的铁毒性SLC7A11。 p65的过表达从阿司匹林诱导的铁铁蛋白中救出了HEPG2和HUH7细胞。 SLC7A11和p65水平高表达水平的HCC患者的存活率较低。从功能上讲，NF-κBp65在体外和体内阻止了阿司匹林诱导的铁毒性作用，Erastin抑制了Erastin。我们得出的结论是，阿司匹林通过限制NF-κB激活的SLC7A11转录来抑制HCC的生长，从而触发了铁毒性。这些结果提供了对阿司匹林在肝癌发生中调节铁凋亡的机制的新见解。阿司匹林和促吞作用诱导剂的结合可能为诊所中HCC治疗的潜在策略提供了潜在的策略。
Abstract
A number of studies have shown that aspirin, as commonly prescribed drug, prevents the development of hepatocellular carcinoma (HCC). Ferroptosis as a dynamic tumor suppressor plays a vital role in hepatocarcinogenesis. In this study we investigated whether aspirin affected ferroptosis in liver cancer cells. RNA-seq analysis revealed that aspirin up-regulated 4 ferroptosis-related drivers and down-regulated 5 ferroptosis-related suppressors in aspirin-treated HepG2 cells. Treatment with aspirin (4 mM) induced remarkable ferroptosis in HepG2 and Huh7 cells, which was enhanced by the ferroptosis inducer erastin (10 μM). We demonstrated that NF-κB p65 restricted ferroptosis in HepG2 and Huh7 cells through directly binding to the core region of SLC7A11 promoter and activating the transcription of ferroptosis inhibitor SLC7A11, whereas aspirin induced ferroptosis through inhibiting NF-κB p65-activated SLC7A11 transcription. Overexpression of p65 rescued HepG2 and Huh7 cells from aspirin-induced ferroptosis. HCC patients with high expression levels of SLC7A11 and p65 presented lower survival rate. Functionally, NF-κB p65 blocked the aspirin-induced ferroptosis in vitro and in vivo, which was attenuated by erastin. We conclude that aspirin triggers ferroptosis by restricting NF-κB-activated SLC7A11 transcription to suppress the growth of HCC. These results provide a new insight into the mechanism by which aspirin regulates ferroptosis in hepatocarcinogenesis. A combination of aspirin and ferroptosis inducer may provide a potential strategy for the treatment of HCC in clinic.