Heme oxygenase-1 accelerates erastin-induced ferroptotic cell death

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.

[1]  M. M. Facchinetti,et al.  Heme oxygenase-1 has antitumoral effects in colorectal cancer: involvement of p53. , 2014, Experimental and molecular pathology.

[2]  H. Nakagawa,et al.  The effect of hemin‐induced oxidative stress on erythropoietin production in HepG2 cells , 2014, Cell biology international.

[3]  H. Maeda,et al.  Upregulation of heme oxygenase-1 in colorectal cancer patients with increased circulation carbon monoxide levels, potentially affects chemotherapeutic sensitivity , 2014, BMC Cancer.

[4]  E. Vazquez,et al.  Heme-oxygenase-1 implications in cell morphology and the adhesive behavior of prostate cancer cells , 2014, Oncotarget.

[5]  W. Shen,et al.  Hydrogen-rich water regulates cucumber adventitious root development in a heme oxygenase-1/carbon monoxide-dependent manner. , 2014, Journal of plant physiology.

[6]  A. Makriyannis,et al.  Inhibition of fatty acid amide hydrolase activates Nrf2 signalling and induces heme oxygenase 1 transcription in breast cancer cells , 2013, British journal of pharmacology.

[7]  B. Stockwell,et al.  Design and synthesis of Pictet-Spengler condensation products that exhibit oncogenic-RAS synthetic lethality and induce non-apoptotic cell death. , 2012, Bioorganic & medicinal chemistry letters.

[8]  D. Richardson,et al.  Sustained expression of heme oxygenase-1 alters iron homeostasis in nonerythroid cells. , 2012, Free radical biology & medicine.

[9]  M. R. Lamprecht,et al.  Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death , 2012, Cell.

[10]  Joshua A. Bittker,et al.  Development of small-molecule probes that selectively kill cells induced to express mutant RAS. , 2012, Bioorganic & medicinal chemistry letters.

[11]  H. Steller,et al.  Programmed Cell Death in Animal Development and Disease , 2011, Cell.

[12]  Dana Pe'er,et al.  Modulatory profiling identifies mechanisms of small molecule-induced cell death , 2011, Proceedings of the National Academy of Sciences.

[13]  J. Cherfils,et al.  Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? , 2010, Nature Reviews Cancer.

[14]  S. Mueller,et al.  Heme oxygenase-1 and iron in liver inflammation: a complex alliance. , 2010, Current drug targets.

[15]  Junying Yuan,et al.  Cyclophilin A release as a biomarker of necrotic cell death , 2010, Cell Death and Differentiation.

[16]  O. Kucuk,et al.  Epigallocatechin-3-gallate activates Nrf2/HO-1 signaling pathway in cisplatin-induced nephrotoxicity in rats. , 2010, Life sciences.

[17]  Junying Yuan,et al.  Necroptosis as an alternative form of programmed cell death. , 2010, Current opinion in cell biology.

[18]  S. Ryter,et al.  Heme oxygenase-1/carbon monoxide: from metabolism to molecular therapy. , 2009, American journal of respiratory cell and molecular biology.

[19]  B. Stockwell,et al.  Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. , 2008, Chemistry & biology.

[20]  M. Ferrándiz,et al.  Inducers of heme oxygenase-1. , 2008, Current pharmaceutical design.

[21]  B. Stockwell,et al.  RAS–RAF–MEK-dependent oxidative cell death involving voltage-dependent anion channels , 2007, Nature.

[22]  Kazuhiro Yoshida,et al.  Heme oxygenase-1 accelerates protumoral effects of nitric oxide in cancer cells , 2005, Virchows Archiv.

[23]  S. yet,et al.  Role of heme oxygenase-1 in cardiovascular function. , 2003, Current pharmaceutical design.

[24]  F. Bach,et al.  Heme oxygenase-1: unleashing the protective properties of heme. , 2003, Trends in immunology.

[25]  William C Hahn,et al.  Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. , 2003, Cancer cell.

[26]  C. Thompson,et al.  Apoptosis in the pathogenesis and treatment of disease , 1995, Science.

[27]  G. Moore,et al.  Haem binding to horse spleen ferritin and its effect on the rate of iron release. , 1992, The Biochemical journal.

[28]  H. Marver,et al.  Microsomal heme oxygenase. Characterization of the enzyme. , 1969, The Journal of biological chemistry.

[29]  H. Marver,et al.  The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. , 1968, Proceedings of the National Academy of Sciences of the United States of America.

[30]  J. Eaton,et al.  Haem oxygenase-1 overexpression alters intracellular iron distribution. , 2013, The Biochemical journal.