Heme oxygenase-1 accelerates erastin-induced ferroptotic cell death

Min-Young Kwon; Eunhee Park; Seon-Jin Lee; Su Wol Chung

doi:10.18632/oncotarget.5162

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Research Papers:

Heme oxygenase-1 accelerates erastin-induced ferroptotic cell death

Min-Young Kwon _, Eunhee Park, Seon-Jin Lee and Su Wol Chung

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Oncotarget. 2015; 6:24393-24403. https://doi.org/10.18632/oncotarget.5162

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Abstract

Min-Young Kwon1, Eunhee Park1, Seon-Jin Lee2,*, Su Wol Chung1,*

1School of Biological Sciences, College of Natural Sciences, University of Ulsan, Ulsan 680-749, South Korea

2Genome Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon 305-806, South Korea

*These authors have contributed equally to this work

Correspondence to:

Su Wol Chung, e-mail: [email protected]

Seon-Jin Lee, e-mail: [email protected]

Keywords: heme oxygenase-1, oncology, oncogene, iron, free radicals

Received: March 11, 2015 Accepted: August 28, 2015 Published: September 10, 2015

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.

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Research Papers:

Heme oxygenase-1 accelerates erastin-induced ferroptotic cell death

Abstract