Heme oxygenase-1 accelerates erastin-induced ferroptotic cell death.
Heme oxygenase-1 accelerates erastin-induced ferroptotic cell death.
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DOI：
10.18632/oncotarget.5162
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发表时间：
2015-09-15
期刊：
影响因子：
--
通讯作者：
Chung SW
中科院分区：
文献类型：
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作者：
Kwon MY;Park E;Lee SJ;Chung SW
致癌RAS选择性致死小分子Erastin触发一种独特的铁依赖性形式的非凋亡性细胞死亡，称为铁凋亡。铁凋亡依赖于细胞内铁依赖性活性氧（ROS）的产生，而不是其他金属。然而，关键的监管机构仍然未知。血红素加氧酶（HO）是细胞内铁的主要来源。在这项研究中，血红素加氧酶的作用，Erastin触发铁凋亡癌细胞死亡进行了调查。锌原卟啉IX（ZnPP），HO-1抑制剂，防止Erastin触发的铁凋亡癌细胞死亡。Erastin还能诱导HT-1080纤维肉瘤细胞HO-1蛋白和mRNA的表达。HO-1+/+和HO-1−/−成纤维细胞、HO-1过表达和chycloheximide处理的实验表明，HO-1的表达在Erastin触发的细胞死亡中具有决定性作用。氯化血红素和CO释放分子（CORM）促进Erastin诱导的铁凋亡细胞死亡，而不是由胆绿素和胆红素。此外，氯化血红素和CORM加速HO-1的表达在Erastin的存在下，增加膜脂质过氧化。因此，HO-1是铁依赖性脂质过氧化过程中的铁凋亡细胞死亡的一个必不可少的酶。
The oncogenic RAS-selective lethal small molecule Erastin triggers a unique iron-dependent form of nonapoptotic cell death termed ferroptosis. Ferroptosis is dependent upon the production of intracellular iron-dependent reactive oxygen species (ROS), but not other metals. However, key regulators remain unknown. The heme oxygenase (HO) is a major intracellular source of iron. In this study, the role of heme oxygenase in Erastin-triggered ferroptotic cancer cell death has been investigated. Zinc protoporphyrin IX (ZnPP), a HO-1 inhibitor, prevented Erastin-triggered ferroptotic cancer cell death. Furthermore, Erastin induced the protein and mRNA levels of HO-1 in HT-1080 fibrosarcoma cells. HO-1+/+ and HO-1−/− fibroblast, HO-1 overexpression, and chycloheximide-treated experiments revealed that the expression of HO-1 has a decisive effects in Erastin-triggered cell death. Hemin and CO-releasing molecules (CORM) promote Erastin-induced ferroptotic cell death, not by biliverdin and bilirubin. In addition, hemin and CORM accelerate the HO-1 expression in the presence of Erastin and increase membranous lipid peroxidation. Thus, HO-1 is an essential enzyme for iron-dependent lipid peroxidation during ferroptotic cell death.