Oncotarget

Research Papers:

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

Alexander J. Lakhter, James Hamilton, Pierre C. Dagher, Suresh Mukkamala, Takashi Hato, X. Charlie Dong, Lindsey D. Mayo, Robert A. Harris, Anantha Shekhar, Mircea Ivan, Nickolay Brustovetsky and Samisubbu R. Naidu _

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Oncotarget. 2014; 5:12694-12703. https://doi.org/10.18632/oncotarget.3031

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Abstract

Alexander J. Lakhter1, James Hamilton2, Pierre C. Dagher3, Suresh Mukkamala1, Takashi Hato3, X. Charlie Dong4, Lindsey D. Mayo5, Robert A. Harris4, Anantha Shekhar6, Mircea Ivan3, Nickolay Brustovetsky2 and Samisubbu R. Naidu1

1 Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana, USA

2 Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA

3 Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA

4 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA

5 Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA

6 Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA

Correspondence:

Samisubbu R. Naidu, email:

Keywords: Ferroxitosis, PKM2, HIF-1α, Warburg effect, melanoma, hypoxia and mitochondria

Received: December 12, 2014 Accepted: December 18, 2014 Published: December 26, 2014

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.


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