2. Academic Validation
  3. mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation

mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation

  • Nat Commun. 2021 Mar 11;12(1):1589. doi: 10.1038/s41467-021-21841-w.
Yilei Zhang 1,  Robert V Swanda 2,  Litong Nie 1,  Xiaoguang Liu 1,  Chao Wang 1,  Hyemin Lee 1,  Guang Lei 1,  Chao Mao 1,  Pranavi Koppula 1 3,  Weijie Cheng 1,  Jie Zhang 1,  Zhenna Xiao 4,  Li Zhuang 1,  Bingliang Fang 5,  Junjie Chen 1,  Shu-Bing Qian 2 6,  Boyi Gan 7 8
Affiliations

Affiliations

  • 1 Department of Experimental Radiation Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2 Graduate Field of Biomedical and Biological Sciences, Cornell University, Ithaca, NY, USA.
  • 3 The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
  • 4 Department of Genetics, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5 Department of Thoracic and Cardiovascular Surgery, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 6 Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
  • 7 Department of Experimental Radiation Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA. bgan@mdanderson.org.
  • 8 The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA. bgan@mdanderson.org.
PMID: 33707434 DOI: 10.1038/s41467-021-21841-w
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.

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