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

Author

Listed:
  • Yilei Zhang

    (the University of Texas MD Anderson Cancer Center)

  • Robert V. Swanda

    (Cornell University)

  • Litong Nie

    (the University of Texas MD Anderson Cancer Center)

  • Xiaoguang Liu

    (the University of Texas MD Anderson Cancer Center)

  • Chao Wang

    (the University of Texas MD Anderson Cancer Center)

  • Hyemin Lee

    (the University of Texas MD Anderson Cancer Center)

  • Guang Lei

    (the University of Texas MD Anderson Cancer Center)

  • Chao Mao

    (the University of Texas MD Anderson Cancer Center)

  • Pranavi Koppula

    (the University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences)

  • Weijie Cheng

    (the University of Texas MD Anderson Cancer Center)

  • Jie Zhang

    (the University of Texas MD Anderson Cancer Center)

  • Zhenna Xiao

    (the University of Texas MD Anderson Cancer Center)

  • Li Zhuang

    (the University of Texas MD Anderson Cancer Center)

  • Bingliang Fang

    (the University of Texas MD Anderson Cancer Center)

  • Junjie Chen

    (the University of Texas MD Anderson Cancer Center)

  • Shu-Bing Qian

    (Cornell University
    Cornell University)

  • Boyi Gan

    (the University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences)

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.

Suggested Citation

  • Yilei Zhang & Robert V. Swanda & Litong Nie & Xiaoguang Liu & Chao Wang & Hyemin Lee & Guang Lei & Chao Mao & Pranavi Koppula & Weijie Cheng & Jie Zhang & Zhenna Xiao & Li Zhuang & Bingliang Fang & Ju, 2021. "mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21841-w
    DOI: 10.1038/s41467-021-21841-w
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    Cited by:

    1. Yuanhui Liu & Nancy G. Azizian & Delaney K. Sullivan & Yulin Li, 2022. "mTOR inhibition attenuates chemosensitivity through the induction of chemotherapy resistant persisters," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Nicolas Millet & Norma V. Solis & Diane Aguilar & Michail S. Lionakis & Robert T. Wheeler & Nicholas Jendzjowsky & Marc Swidergall, 2022. "IL-23 signaling prevents ferroptosis-driven renal immunopathology during candidiasis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Mihee Oh & Seo Young Jang & Ji-Yoon Lee & Jong Woo Kim & Youngae Jung & Jiwoo Kim & Jinho Seo & Tae-Su Han & Eunji Jang & Hye Young Son & Dain Kim & Min Wook Kim & Jin-Sung Park & Kwon-Ho Song & Kyoun, 2023. "The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Yuelong Yan & Hongqi Teng & Qinglei Hang & Lavanya Kondiparthi & Guang Lei & Amber Horbath & Xiaoguang Liu & Chao Mao & Shiqi Wu & Li Zhuang & M. James You & Masha V. Poyurovsky & Li Ma & Kellen Olsze, 2023. "SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    5. Pranavi Koppula & Guang Lei & Yilei Zhang & Yuelong Yan & Chao Mao & Lavanya Kondiparthi & Jiejun Shi & Xiaoguang Liu & Amber Horbath & Molina Das & Wei Li & Masha V. Poyurovsky & Kellen Olszewski & B, 2022. "A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. Xinyi Shan & Jiahuan Li & Jiahao Liu & Baoli Feng & Ting Zhang & Qian Liu & Huixin Ma & Honghong Wu & Hao Wu, 2023. "Targeting ferroptosis by poly(acrylic) acid coated Mn3O4 nanoparticles alleviates acute liver injury," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    7. Hyemin Lee & Amber Horbath & Lavanya Kondiparthi & Jitendra Kumar Meena & Guang Lei & Shayani Dasgupta & Xiaoguang Liu & Li Zhuang & Pranavi Koppula & Mi Li & Iqbal Mahmud & Bo Wei & Philip L. Lorenzi, 2024. "Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    8. Xin Chen & Jun Huang & Chunhua Yu & Jiao Liu & Wanli Gao & Jingbo Li & Xinxin Song & Zhuan Zhou & Changfeng Li & Yangchun Xie & Guido Kroemer & Jinbao Liu & Daolin Tang & Rui Kang, 2022. "A noncanonical function of EIF4E limits ALDH1B1 activity and increases susceptibility to ferroptosis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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