Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism

Ferroptosis is mediated by lipid peroxidation of phospholipids containing polyunsaturated fatty acyl moieties. Glutathione, the key cellular antioxidant capable of inhibiting lipid peroxidation via the activity of the enzyme glutathione peroxidase 4 (GPX-4), is generated directly from the sulfur-containing amino acid cysteine, and indirectly from methionine via the transsulfuration pathway. Herein we show that cysteine and methionine deprivation (CMD) can synergize with the GPX4 inhibitor RSL3 to increase ferroptotic cell death and lipid peroxidation in both murine and human glioma cell lines and in ex vivo organotypic slice cultures. We also show that a cysteine-depleted, methionine-restricted diet can…

• NI
  National Institutes of Health

  Awards: UL1TR001873, R35CA209896, P30CA013696, P01CA87497, Support Grant P30CA013696, R01NS103473, R61NS109407, S10RR025686
• WC
  Weill Cornell Medical College
• NC
  National Cancer Institute

  Awards: UL1TR001873, R35CA209896, P01CA87497, P30CA013696
• NI
  National Institute of Neurological Disorders and Stroke

  Awards: R61NS109407, R01NS103473
• NC
  National Center for Advancing Translational Sciences

  Awards: UL1TR001873, P30CA013696