Lakhter, Alexander J.Hamilton, JamesDagher, Pierre C.Mukkamala, SureshHato, TakashiDong, X. CharlieMayo, Lindsey D.Harris, Robert A.Shekhar, AnanthaIvan, MirceaBrustovetsky, NickolayNaidu, Samisubbu R.2016-09-162016-09-162014-12-30Lakhter, A. J., Hamilton, J., Dagher, P. C., Mukkamala, S., Hato, T., Dong, X. C., … Naidu, S. R. (2014). Ferroxitosis: A cell death from modulation of oxidative phosphorylation and PKM2-dependent glycolysis in melanoma. Oncotarget, 5(24), 12694–12703.1949-2553https://hdl.handle.net/1805/10939Reliance 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.en-USAttribution 4.0 InternationalCarrier ProteinsmetabolismIron Chelating AgentspharmacologyMelanomadrug therapyMembrane ProteinsThyroid HormonesVitamin K 3pharmacologyArticle