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MTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation

ABSTRACT: 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.

INSTRUMENT(S): QE-HF-x

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Yilei Zhang

PROVIDER: MSV000086009 | MassIVE | Tue Aug 25 09:09:00 BST 2020

REPOSITORIES: MassIVE

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