Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers

Nat Chem Biol. 2020 Dec;16(12):1351-1360. doi: 10.1038/s41589-020-0613-y. Epub 2020 Aug 10.

Abstract

Cancer cells rewire their metabolism and rely on endogenous antioxidants to mitigate lethal oxidative damage to lipids. However, the metabolic processes that modulate the response to lipid peroxidation are poorly defined. Using genetic screens, we compared metabolic genes essential for proliferation upon inhibition of cystine uptake or glutathione peroxidase-4 (GPX4). Interestingly, very few genes were commonly required under both conditions, suggesting that cystine limitation and GPX4 inhibition may impair proliferation via distinct mechanisms. Our screens also identify tetrahydrobiopterin (BH4) biosynthesis as an essential metabolic pathway upon GPX4 inhibition. Mechanistically, BH4 is a potent radical-trapping antioxidant that protects lipid membranes from autoxidation, alone and in synergy with vitamin E. Dihydrofolate reductase catalyzes the regeneration of BH4, and its inhibition by methotrexate synergizes with GPX4 inhibition. Altogether, our work identifies the mechanism by which BH4 acts as an endogenous antioxidant and provides a compendium of metabolic modifiers of lipid peroxidation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antioxidants / pharmacology
  • Biopterins / analogs & derivatives
  • Biopterins / pharmacology
  • Carbolines / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cystine / antagonists & inhibitors
  • Cystine / metabolism*
  • Dose-Response Relationship, Drug
  • Ferroptosis / drug effects
  • Ferroptosis / genetics*
  • Folic Acid Antagonists / pharmacology
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Jurkat Cells
  • Lipid Peroxidation / drug effects
  • Methotrexate / pharmacology
  • Oxidative Stress
  • Phospholipid Hydroperoxide Glutathione Peroxidase / antagonists & inhibitors
  • Phospholipid Hydroperoxide Glutathione Peroxidase / genetics*
  • Phospholipid Hydroperoxide Glutathione Peroxidase / metabolism
  • Piperazines / pharmacology
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Tetrahydrofolate Dehydrogenase / genetics*
  • Tetrahydrofolate Dehydrogenase / metabolism
  • Vitamin E / pharmacology

Substances

  • Antineoplastic Agents
  • Antioxidants
  • Carbolines
  • Folic Acid Antagonists
  • Piperazines
  • RSL3 compound
  • Reactive Oxygen Species
  • erastin
  • Vitamin E
  • Biopterins
  • Cystine
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • Tetrahydrofolate Dehydrogenase
  • sapropterin
  • Methotrexate