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, we perform integrated proteomic and functional analyses to reveal that SLC7A11-mediated cystine uptake promotes not only GSH synthesis, but also GPX4 protein synthesis. Mechanistically, we find that cyst(e)ine activates mechanistic/mammalian target of rapamycin complex 1 (mTORC1) and promotes GPX4 protein synthesis at least partly through the Rag-mTORC1-4EBP signaling axis. We show that pharmacologic inhibition of mTORC1 decreases GPX4 protein levels, sensitizes cancer cells to ferroptosis, and synergizes with ferroptosis inducers to suppress patient-derived xenograft tumor growth in vivo. Together, our results reveal a regulatory mechanism to coordinate GPX4 protein synthesis with cyst(e)ine availability and suggest using combinatorial therapy of mTORC1 inhibitors and ferroptosis inducers in cancer treatment.
Highlights
Glutathione peroxidase 4 (GPX4) utilizes glutathione (GSH) to detoxify lipid peroxidation and plays an essential role in inhibiting ferroptosis
One key signaling node that integrates a wide range of environmental cues to regulate protein synthesis is mechanistic target of rapamycin complex 118–21. mammalian target of rapamycin complex 1 (mTORC1) exists as a multiprotein complex consisting of mTOR, Raptor, and other proteins18,19. mTORC1 can be potently activated by amino acids, growth factors, or glucose, among other stimuli
We showed that AZD8055, but not rapamycin, sensitized cancer cells to ferroptosis induced by class 2 ferroptosis inducers (FINs) (Supplementary Fig. 6e–f), consistent with the differential effects of these mTORC1 inhibitors on 4E (eIF4E)-binding proteins (4EBPs) phosphorylation and GPX4 levels
Summary
Glutathione peroxidase 4 (GPX4) utilizes glutathione (GSH) to detoxify lipid peroxidation and plays an essential role in inhibiting ferroptosis. Our results reveal a regulatory mechanism to coordinate GPX4 protein synthesis with cyst(e)ine availability and suggest using combinatorial therapy of mTORC1 inhibitors and ferroptosis inducers in cancer treatment. Compared with cystine starvation or FIN treatment, GSH depletion generally results in much milder ferroptosis phenotype (or even does not induce obvious cell death in some cell lines)[12], indicating that there might exist additional mechanisms linking SLC7A11-mediated cystine transport to GPX4 function in ferroptosis regulation. We show that cyst(e)ine promotes GSH biosynthesis, and promotes GPX4 protein synthesis through activating mTORC1 (in this manuscript, we use the term “cyst(e)ine” to refer to “cystine and cysteine”), and that mTORC1 inactivation sensitizes cancer cells to ferroptosis by decreasing GPX4 synthesis, revealing a crosstalk between mTORC1 and ferroptosis
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