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

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. Chaudhary, Lillian Liao, Michael Argenziano, Tejaswi Sudhakar, Colin P. Sperring, Benjamin L. Shapiro, Eman R. Ahmed, Connor Kinslow, Ling F. Ye, Markus D. Siegelin, Simon Cheng, Rajesh Soni, Jeffrey N. Bruce, Brent R. Stockwell and Peter Canoll ()
Additional contact information
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
Peter Canoll: Columbia University Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36630-w

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