title: Ferroxitosis: a cell death from modulation of oxidative phosphorylation and PKM2-dependent glycolysis in melanoma.
abstract: Reliance on glycolysis is a characteristic of malignancy, yet the development of resistance to BRAF inhibitors in melanoma is associated with gain of mitochondrial function. Concurrent attenuation of oxidative phosphorylation and HIF-1α/PKM2-dependent glycolysis promotes a non-apoptotic, iron- and oxygen-dependent cell death that we term ferroxitosis. The redox cycling agent menadione causes a robust increase in oxygen consumption, accompanied by significant loss of intracellular ATP and rapid cell death. Conversely, either hypoxic adaptation or iron chelation prevents menadione-induced ferroxitosis. Ectopic expression of K213Q HIF-1α mutant blunts the effects of menadione. However, knockdown of HIF-1α or PKM2 restores menadione-induced cytotoxicity in hypoxia. Similarly, exposure of melanoma cells to shikonin, a menadione analog and a potential PKM2 inhibitor, is sufficient to induce ferroxitosis under hypoxic conditions. Collectively, our findings reveal that ferroxitosis curtails metabolic plasticity in melanoma.
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lakhter
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: James
authors.initials: J
authors.lastname: Hamilton
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Pierre C
authors.initials: PC
authors.lastname: Dagher
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Suresh
authors.initials: S
authors.lastname: Mukkamala
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hato
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: X Charlie
authors.initials: XC
authors.lastname: Dong
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Lindsey D
authors.initials: LD
authors.lastname: Mayo
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Anantha
authors.initials: A
authors.lastname: Shekhar
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Mircea
authors.initials: M
authors.lastname: Ivan
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Nickolay
authors.initials: N
authors.lastname: Brustovetsky
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Samisubbu R
authors.initials: SR
authors.lastname: Naidu
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010085:Oxidative Phosphorylation; D011897:Random Allocation; D013963:Thyroid Hormones / Q000378:metabolism*; D014162:Transfection; D024483:Vitamin K 3 / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents; D008565:Membrane Proteins; D013963:Thyroid Hormones; D024483:Vitamin K 3; D000097810:Thyroid Hormone-Binding Proteins