@article{e60608c91c694dd0a74e4215bf7243cf,
title = "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, 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.",
author = "Yilei Zhang and Swanda, {Robert V.} and Litong Nie and Xiaoguang Liu and Chao Wang and Hyemin Lee and Guang Lei and Chao Mao and Pranavi Koppula and Weijie Cheng and Jie Zhang and Zhenna Xiao and Li Zhuang and Bingliang Fang and Junjie Chen and Qian, {Shu Bing} and Boyi Gan",
note = "Funding Information: This research has been supported by Institutional Research Fund from The University of Texas MD Anderson Cancer Center, KC180131 from Department of Defense Kidney Cancer Research Program, R01CA181196, R01CA244144, and R01CA247992 from the National Institutes of Health (to B.G.). B.G. is an Andrew Sabin Family Fellow. P.K. is supported by CPRIT Research Training Grant (RP170067) and Dr. John J. Kopchick Research Award from The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences. Work in the lab of S.-B.Q. is supported by NIH grants R01GM1222814 and R21CA227917 and by the Howard Hughes Medical Institute (55108556). R. S. is supported by an NIH, National Institute of General Medical Sciences, Chemical Biology Interface (CBI) Training Grant (T32GM008500). PDX generation and annotation were supported by the University of Texas MD Anderson Cancer Center Moon Shots Program, Specialized Program of Research Excellence (SPORE) grant CA070907, and University of Texas PDX Development and Trial Center grant U54CA224065. This research has also been supported by the National Institutes of Health Cancer Center Support Grant P30CA016672 to The University of Texas MD Anderson Cancer Center. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
day = "1",
doi = "10.1038/s41467-021-21841-w",
language = "English (US)",
volume = "12",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Research",
number = "1",
}