Abstract
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.
Highlights
Cell death is crucial for normal development, homeostasis, and the prevention of hyperproliferative diseases such as cancer [1, 2]
We describe that Erastin induces heme oxygenase (HO)-1 expression in HT-1080 fibrosarcoma cells and overexpressed Heme oxygenase-1 (HO-1) accelerates Erastin-triggered ferroptotic cell death
Yang WS and his colleagues reported the identification of additional small molecules, RSL3, ML162, and DPI10 [5, 22], that display oncogenicRAS-synthetic-lethality in engineered fibroblast-derived tumorigenic cell lines
Summary
Cell death is crucial for normal development, homeostasis, and the prevention of hyperproliferative diseases such as cancer [1, 2]. RSL-induced death is, associated with increased levels of intracellular reactive oxygen species (ROS) and is prevented by iron chelation or genetic inhibition of cellular iron uptake [5, 6]. In a recent systematic study of various mechanistically unique lethal compounds, the prevention of cell death by iron chelation was a rare phenomenon [7], suggesting that few triggers can access iron-dependent lethal mechanisms. They find that Erastin-induced death involves a unique constellation of morphological, biochemical, and genetic features, which led Stockwell and colleagues to propose the name ferroptosis as a description for this phenotype. Ferroptosis involves metabolic dysfunction that results in the production of both cytosolic and lipid ROS, independent of mitochondria but dependent on NADPH oxidases in some cell contexts [8]
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