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

Alexander J. Lakhter, James Hamilton, Pierre Dagher, Suresh Mukkamala, Takashi Hato, X. Dong, Lindsey Mayo, Robert Harris, Anantha Shekhar, Mircea Ivan, Nikolai Broustovetski, Samisubbu Naidu

Research output: Contribution to journalArticle

8 Citations (Scopus)

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-1a/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-1a 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.

Original languageEnglish
Pages (from-to)12694-12703
Number of pages10
JournalOncotarget
Volume5
Issue number24
StatePublished - 2014

Fingerprint

Vitamin K 3
Oxidative Phosphorylation
Glycolysis
Melanoma
Cell Death
Iron
Oxygen Consumption
Oxidation-Reduction
Adenosine Triphosphate
Oxygen
Neoplasms

Keywords

  • Ferroxitosis
  • HIF-1α
  • Hypoxia and mitochondria
  • Melanoma
  • PKM2
  • Warburg effect

ASJC Scopus subject areas

  • Oncology

Cite this

Lakhter, A. J., Hamilton, J., Dagher, P., Mukkamala, S., Hato, T., Dong, X., ... Naidu, S. (2014). Ferroxitosis: A cell death from modulation of oxidative phosphorylation and PKM2-dependent glycolysis in melanoma. Oncotarget, 5(24), 12694-12703.

Ferroxitosis : A cell death from modulation of oxidative phosphorylation and PKM2-dependent glycolysis in melanoma. / Lakhter, Alexander J.; Hamilton, James; Dagher, Pierre; Mukkamala, Suresh; Hato, Takashi; Dong, X.; Mayo, Lindsey; Harris, Robert; Shekhar, Anantha; Ivan, Mircea; Broustovetski, Nikolai; Naidu, Samisubbu.

In: Oncotarget, Vol. 5, No. 24, 2014, p. 12694-12703.

Research output: Contribution to journalArticle

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