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DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer

Author

Listed:
  • Chao Mao

    (The University of Texas MD Anderson Cancer Center)

  • Xiaoguang Liu

    (The University of Texas MD Anderson Cancer Center)

  • Yilei Zhang

    (The University of Texas MD Anderson Cancer Center)

  • Guang Lei

    (The University of Texas MD Anderson Cancer Center)

  • Yuelong Yan

    (The University of Texas MD Anderson Cancer Center)

  • Hyemin Lee

    (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)

  • Shiqi Wu

    (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)

  • Masha V. Poyurovsky

    (Kadmon Corporation, LLC)

  • Kellen Olszewski

    (Kadmon Corporation, LLC)

  • Boyi Gan

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

Abstract

Ferroptosis, a form of regulated cell death that is induced by excessive lipid peroxidation, is a key tumour suppression mechanism1–4. Glutathione peroxidase 4 (GPX4)5,6 and ferroptosis suppressor protein 1 (FSP1)7,8 constitute two major ferroptosis defence systems. Here we show that treatment of cancer cells with GPX4 inhibitors results in acute depletion of N-carbamoyl-l-aspartate, a pyrimidine biosynthesis intermediate, with concomitant accumulation of uridine. Supplementation with dihydroorotate or orotate—the substrate and product of dihydroorotate dehydrogenase (DHODH)—attenuates or potentiates ferroptosis induced by inhibition of GPX4, respectively, and these effects are particularly pronounced in cancer cells with low expression of GPX4 (GPX4low). Inactivation of DHODH induces extensive mitochondrial lipid peroxidation and ferroptosis in GPX4low cancer cells, and synergizes with ferroptosis inducers to induce these effects in GPX4high cancer cells. Mechanistically, DHODH operates in parallel to mitochondrial GPX4 (but independently of cytosolic GPX4 or FSP1) to inhibit ferroptosis in the mitochondrial inner membrane by reducing ubiquinone to ubiquinol (a radical-trapping antioxidant with anti-ferroptosis activity). The DHODH inhibitor brequinar selectively suppresses GPX4low tumour growth by inducing ferroptosis, whereas combined treatment with brequinar and sulfasalazine, an FDA-approved drug with ferroptosis-inducing activity, synergistically induces ferroptosis and suppresses GPX4high tumour growth. Our results identify a DHODH-mediated ferroptosis defence mechanism in mitochondria and suggest a therapeutic strategy of targeting ferroptosis in cancer treatment.

Suggested Citation

  • Chao Mao & Xiaoguang Liu & Yilei Zhang & Guang Lei & Yuelong Yan & Hyemin Lee & Pranavi Koppula & Shiqi Wu & Li Zhuang & Bingliang Fang & Masha V. Poyurovsky & Kellen Olszewski & Boyi Gan, 2021. "DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer," Nature, Nature, vol. 593(7860), pages 586-590, May.
  • Handle: RePEc:nat:nature:v:593:y:2021:i:7860:d:10.1038_s41586-021-03539-7
    DOI: 10.1038/s41586-021-03539-7
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    Cited by:

    1. Yun Lv & Chunhui Liang & Qichao Sun & Jing Zhu & Haiyan Xu & Xiaoqing Li & Yao-yao Li & Qihai Wang & Huiqing Yuan & Bo Chu & Deyu Zhu, 2023. "Structural insights into FSP1 catalysis and ferroptosis inhibition," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Kui Xiao & Niyuan Zhang & Feifei Li & Dayong Hou & Xiaoyi Zhai & Wanhai Xu & Gelin Wang & Hao Wang & Liang Zhao, 2022. "Pro-oxidant response and accelerated ferroptosis caused by synergetic Au(I) release in hypercarbon-centered gold(I) cluster prodrugs," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Yandi Wu & Tongsheng Huang & Xinghui Li & Conghui Shen & Honglin Ren & Haiping Wang & Teng Wu & Xinlu Fu & Shijie Deng & Ziqi Feng & Shijie Xiong & Hui Li & Saifei Gao & Zhenyu Yang & Fei Gao & Lele D, 2023. "Retinol dehydrogenase 10 reduction mediated retinol metabolism disorder promotes diabetic cardiomyopathy in male mice," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. 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.
    5. Da-Yun Jin & Xuejie Chen & Yizhou Liu & Craig M. Williams & Lars C. Pedersen & Darrel W. Stafford & Jian-Ke Tie, 2023. "A genome-wide CRISPR-Cas9 knockout screen identifies FSP1 as the warfarin-resistant vitamin K reductase," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    6. Dadi Jiang & Youming Guo & Tianyu Wang & Liang Wang & Yuelong Yan & Ling Xia & Rakesh Bam & Zhifen Yang & Hyemin Lee & Takao Iwawaki & Boyi Gan & Albert C. Koong, 2024. "IRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    7. 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.
    8. 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.
    9. Wei Yang & Bo Mu & Jing You & Chenyu Tian & Huachao Bin & Zhiqiang Xu & Liting Zhang & Ronggang Ma & Ming Wu & Guo Zhang & Chong Huang & Linli Li & Zhenhua Shao & Lunzhi Dai & Laurent Désaubry & Sheng, 2022. "Non-classical ferroptosis inhibition by a small molecule targeting PHB2," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    10. Guowei Li & Shihui Jiang & Aijun Liu & Lixiang Ye & Jianxi Ke & Caiping Liu & Lian Chen & Yongsheng Liu & Maochun Hong, 2023. "Proof of crystal-field-perturbation-enhanced luminescence of lanthanide-doped nanocrystals through interstitial H+ doping," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    11. 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.
    12. Guoshu Bi & Jiaqi Liang & Yunyi Bian & Guangyao Shan & Yiwei Huang & Tao Lu & Huan Zhang & Xing Jin & Zhencong Chen & Mengnan Zhao & Hong Fan & Qun Wang & Boyi Gan & Cheng Zhan, 2024. "Polyamine-mediated ferroptosis amplification acts as a targetable vulnerability in cancer," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    13. M. T. Herrera-Abreu & J. Guan & U. Khalid & J. Ning & M. R. Costa & J. Chan & Q. Li & J-P. Fortin & W. R. Wong & P. Perampalam & A. Biton & W. Sandoval & J. Vijay & M. Hafner & R. Cutts & G. Wilson & , 2024. "Inhibition of GPX4 enhances CDK4/6 inhibitor and endocrine therapy activity in breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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