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

Area of Science:

• Biochemistry
• Cell Biology
• Oncology

Background:

• Malignancy often relies on glycolysis.
• BRAF inhibitor resistance in melanoma is linked to increased mitochondrial function.
• Metabolic plasticity is crucial for cancer cell survival and drug resistance.

Purpose of the Study:

• To investigate a novel cell death mechanism in melanoma.
• To explore the role of metabolic pathways in BRAF inhibitor resistance.
• To identify therapeutic strategies targeting melanoma's metabolic vulnerabilities.

Main Methods:

• Induction of cell death using menadione and shikonin.
• Manipulation of hypoxia-inducible factor 1-alpha (HIF-1α) and pyruvate kinase M2 (PKM2) levels.
• Assessment of oxidative phosphorylation, ATP levels, and intracellular iron.

Main Results:

• Concurrent inhibition of oxidative phosphorylation and HIF-1α/PKM2-dependent glycolysis induces ferroxitosis, an iron- and oxygen-dependent cell death.
• Menadione triggers ferroxitosis by increasing oxygen consumption, leading to ATP depletion and cell death.
• Hypoxic adaptation or iron chelation protects against menadione-induced ferroxitosis.
• Modulating HIF-1α and PKM2 affects menadione-induced cell death, particularly under hypoxic conditions.

Conclusions:

• Ferroxitosis represents a novel cell death pathway in melanoma.
• Targeting metabolic pathways like glycolysis and oxidative phosphorylation can overcome BRAF inhibitor resistance.
• Ferroxitosis curtails metabolic plasticity, offering a potential therapeutic strategy for melanoma.