title: Heme oxygenase-1 accelerates erastin-induced ferroptotic cell death.
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.
authors.affiliation: School of Biological Sciences, College of Natural Sciences, University of Ulsan, Ulsan 680-749, South Korea.
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Kwon
authors.affiliation: School of Biological Sciences, College of Natural Sciences, University of Ulsan, Ulsan 680-749, South Korea.
authors.forename: Eunhee
authors.initials: E
authors.lastname: Park
authors.affiliation: Genome Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon 305-806, South Korea.
authors.forename: Seon-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: School of Biological Sciences, College of Natural Sciences, University of Ulsan, Ulsan 680-749, South Korea.
authors.forename: Su Wol
authors.initials: SW
authors.lastname: Chung
mesh_terms: D000818:Animals; D001663:Bilirubin / Q000737:chemistry; D001664:Biliverdine / Q000737:chemistry; D016923:Cell Death; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003513:Cycloheximide / Q000737:chemistry; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006427:Hemin / Q000737:chemistry; D006801:Humans; D007501:Iron / Q000737:chemistry*; D015227:Lipid Peroxidation; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010879:Piperazines / Q000737:chemistry*; D011524:Protoporphyrins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D010879:Piperazines; D011524:Protoporphyrins; D017382:Reactive Oxygen Species; C477224:erastin; C017803:zinc protoporphyrin; D006427:Hemin; D003513:Cycloheximide; D007501:Iron; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D001664:Biliverdine; D001663:Bilirubin
keywords: free radicals; heme oxygenase-1; iron; oncogene; oncology