Description
Glutathione peroxidase 4 (GPX4) utilizes glutathione (GSH) to detoxify lipid peroxidation and
plays an essential role in inhibiting ferroptosis. As a selenoprotein, GPX4 protein synthesis is
highly inefficient and energetically costly. How cells coordinate GPX4 synthesis with nutrient
availability remains unclear. In this study, integrated proteomic and functional analyses reveal
that SLC7A11-mediated cystine uptake promotes not only GSH synthesis but also GPX4 protein synthesis. Mechanistically, cyst(e)ine activates mechanistic/mammalian target of rapamycin complex 1 (mTORC1) and promotes GPX4 protein synthesis at least partly through the mTORC1-4E-BP signaling axis. Pharmacologic inhibition of mTORC1 decreases GPX4 protein levels, sensitizes cancer cells to ferroptosis, and synergizes with ferroptosis inducers (FINs) to suppress patient-derived xenograft tumor growth in vivo. Together, our results reveal a hitherto unrecognized regulatory mechanism to coordinate GPX4 protein synthesis with cyst(e)ine availability and suggest to use the combination of mTORC1 inhibitors and FINs in cancer treatment.
[doi:10.25345/C58759]
Keywords: ferroptosis, cysteine, cystine, GPX4, mTORC1, protein synthesis, cancer treatment
Contact
Principal Investigators:
(in alphabetical order)
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Yilei Zhang, The University of Texas MD Anderson Cancer Center, United States
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Submitting User: |
Litong
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Originally identified proteins that were automatically
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Number of distinct proteins quantified across all analyses (original submission and reanalyses)
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Distinct protein accessions are counted across all files submitted in the "Statistical Analysis
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Number of distinct proteins found to be differentially abundant in at least one comparison
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A protein is differentially abundant if its change in abundance across conditions is found
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Distinct protein accessions are counted across all files submitted in the "Statistical Analysis
of Quantified Analytes" category having a "Protein" column in this dataset.
"N/A" means no results of this type were submitted.
This dataset may not contain all raw spectra data as originally deposited in PRIDE.
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