Ferroxitosis: a cell death from modulation of oxidative phosphorylation and PKM2-dependent glycolysis in melanoma

• Published in: Oncotarget Vol. 5; no. 24; pp. 12694 - 12703
• Main Authors: Lakhter, Alexander J, Hamilton, James, Dagher, Pierre C, Mukkamala, Suresh, Hato, Takashi, Dong, X Charlie, Mayo, Lindsey D, Harris, Robert A, Shekhar, Anantha, Ivan, Mircea, Brustovetsky, Nickolay, Naidu, Samisubbu R
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 30.12.2014
• Subjects: Animals; Carrier Proteins - metabolism; Cell Death - physiology; Cell Hypoxia - physiology; Cell Line, Tumor; Cell Proliferation - physiology; Glycolysis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Iron Chelating Agents - pharmacology; Male; Melanoma - drug therapy; Melanoma - metabolism; Membrane Proteins - metabolism; Mice; Mice, Inbred NOD; Mice, SCID; Oxidative Phosphorylation; Random Allocation; Research Paper; Thyroid Hormone-Binding Proteins; Thyroid Hormones - metabolism; Transfection; Vitamin K 3 - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.3031

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.