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

Author

Listed:
  • Pavan S. Upadhyayula

    (Columbia University Medical Center)

  • Dominique M. Higgins

    (Columbia University Medical Center)

  • Angeliki Mela

    (Columbia University Medical Center)

  • Matei Banu

    (Columbia University Medical Center)

  • Athanassios Dovas

    (Columbia University Medical Center)

  • Fereshteh Zandkarimi

    (Columbia University)

  • Purvi Patel

    (Columbia University Medical Center)

  • Aayushi Mahajan

    (Columbia University Medical Center)

  • Nelson Humala

    (Columbia University Medical Center)

  • Trang T. T. Nguyen

    (Columbia University Medical Center)

  • Kunal R. Chaudhary

    (Columbia University Medical Center)

  • Lillian Liao

    (Columbia University Medical Center)

  • Michael Argenziano

    (Columbia University Medical Center)

  • Tejaswi Sudhakar

    (Columbia University Medical Center)

  • Colin P. Sperring

    (Columbia University Medical Center)

  • Benjamin L. Shapiro

    (Columbia University Medical Center)

  • Eman R. Ahmed

    (Columbia University)

  • Connor Kinslow

    (Columbia University)

  • Ling F. Ye

    (Columbia University Medical Center)

  • Markus D. Siegelin

    (Columbia University Medical Center)

  • Simon Cheng

    (Columbia University)

  • Rajesh Soni

    (Columbia University Medical Center)

  • Jeffrey N. Bruce

    (Columbia University Medical Center)

  • Brent R. Stockwell

    (Columbia University
    Columbia University)

  • Peter Canoll

    (Columbia University Medical Center)

Abstract

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 improve therapeutic response to RSL3 and prolong survival in a syngeneic orthotopic murine glioma model. Finally, this CMD diet leads to profound in vivo metabolomic, proteomic and lipidomic alterations, highlighting the potential for improving the efficacy of ferroptotic therapies in glioma treatment with a non-invasive dietary modification.

Suggested Citation

  • Pavan S. Upadhyayula & Dominique M. Higgins & Angeliki Mela & Matei Banu & Athanassios Dovas & Fereshteh Zandkarimi & Purvi Patel & Aayushi Mahajan & Nelson Humala & Trang T. T. Nguyen & Kunal R. Chau, 2023. "Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36630-w
    DOI: 10.1038/s41467-023-36630-w
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    References listed on IDEAS

    as
    1. Jiska Reest & Sergio Lilla & Liang Zheng & Sara Zanivan & Eyal Gottlieb, 2018. "Proteome-wide analysis of cysteine oxidation reveals metabolic sensitivity to redox stress," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    2. David S. Liu & Cuong P. Duong & Sue Haupt & Karen G. Montgomery & Colin M. House & Walid J. Azar & Helen B. Pearson & Oliver M. Fisher & Matthew Read & Glen R. Guerra & Ygal Haupt & Carleen Cullinane , 2017. "Inhibiting the system xC−/glutathione axis selectively targets cancers with mutant-p53 accumulation," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
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