Brusatol induces ferroptosis in oesophageal squamous cell carcinoma by repressing GSH synthesis and increasing the labile iron pool via inhibition of the NRF2 pathway.
Brusatol induces ferroptosis in oesophageal squamous cell carcinoma by repressing GSH synthesis and increasing the labile iron pool via inhibition of the NRF2 pathway.
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DOI：
10.1016/j.biopha.2023.115567
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发表时间：
2023-09
期刊：
影响因子：
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通讯作者：
Xu Zhu;Nannan Huang;Yao Ji;Xinling Sheng;Juanjuan Huo;Yuan Zhu;Menghuan Huang;Wei He
中科院分区：
文献类型：
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作者：
Xu Zhu;Nannan Huang;Yao Ji;Xinling Sheng;Juanjuan Huo;Yuan Zhu;Menghuan Huang;Wei He
鸦胆子醇（Bru）是一种存在于鸦胆子（Brucea sumatrana）中的生物活性化合物，对多种恶性肿瘤具有抗肿瘤作用。然而，Bru在食管鳞状细胞癌（ESCC）中的作用和分子机制仍不清楚。在这里，我们发现Bru降低了ESCC细胞的存活率。随后，铁凋亡抑制剂，去铁胺和利司他汀-1，挽救了Bru诱导的细胞死亡，表明铁凋亡在Bru诱导的细胞死亡中起主要作用。此外，布鲁促进脂质过氧化，谷胱甘肽（GSH）耗竭，和亚铁超载在体外。与这些体外结果一致，Bru通过触发铁凋亡显著抑制KYSE 150异种移植裸鼠的肿瘤生长。机制上，核因子E2相关因子2（NRF 2）通过增加泛素-蛋白酶体降解失活被发现是布鲁诱导的铁凋亡的重要决定因素。值得注意的是，Bru通过下调NRF 2靶基因的表达，显著降低GSH合成、铁储存和外排。（谷氨酸-半胱氨酸连接酶催化亚基（GCLC）、溶质载体家族7成员11（SLC 7A 11）、铁蛋白重链1（FTH 1）和溶质载体家族40成员1（SLC 40 A1）），导致致死的基于脂质的活性氧物质（ROS）的积累和螯合铁的细胞内富集。综上所述，我们的研究结果表明，铁凋亡是一种新的机制，Bru诱导的抗肿瘤活性，并有望提供一个有价值的化合物ESCC治疗。
Brusatol (Bru), a bioactive compound found inBrucea sumatrana,exerts antitumour effects on several malignancies. However, the role and molecular mechanism of Bru in squamous cell carcinoma of the oesophagus (ESCC) remain unclear. Here, we found that Bru decreased the survival of ESCC cells. Subsequently, the ferroptosis inhibitors, deferoxamine and liproxstatin-1, rescued Bru-induced cell death, indicating that ferroptosis plays a major role in Bru-induced cell death. Furthermore, Bru promoted lipid peroxidation, glutathione (GSH) depletion, and ferrous iron overloadin vitro. Consistent with thesein vitroresults, Bru significantly inhibited tumour growth in KYSE150 xenograft nude mice by triggering ferroptosis. Mechanistically, nuclear factor E2-related factor 2 (NRF2) inactivationviaincreased ubiquitin-proteasome degradation was found to be a vital determinant of ferroptosis induced by Bru. Notably, Bru significantly decreases GSH synthesis, iron storage, and efflux by downregulating the expression of NRF2 target genes (glutamate-cysteine ligase catalytic subunit (GCLC), solute carrier family 7 member 11 (SLC7A11), ferritin heavy chain 1 (FTH1), and solute carrier family 40 member 1 (SLC40A1)), resulting in the accumulation of lethal lipid-based reactive oxygen species (ROS) and intracellular enrichment of chelated iron. Taken together, our findings indicate that ferroptosis is a novel mechanism underlying Bru-induced antitumour activity and will hopefully provide a valuable compound for ESCC treatment.