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Lysyl oxidase-like 3 restrains mitochondrial ferroptosis to promote liver cancer chemoresistance by stabilizing dihydroorotate dehydrogenase

Author

Listed:
  • Meixiao Zhan

    (Zhuhai People’s Hospital, Zhuhai Hospital affiliated with Jinan University, Zhuhai)

  • Yufeng Ding

    (Guangzhou University)

  • Shanzhou Huang

    (Guangdong Academy of Medical Sciences)

  • Yuhang Liu

    (Guangzhou University)

  • Jing Xiao

    (Zhuhai People’s Hospital, Zhuhai Hospital affiliated with Jinan University, Zhuhai)

  • Hua Yu

    (Guangzhou University)

  • Ligong Lu

    (Zhuhai People’s Hospital, Zhuhai Hospital affiliated with Jinan University, Zhuhai)

  • Xiongjun Wang

    (Guangzhou University)

Abstract

To overcome chemotherapy resistance, novel strategies sensitizing cancer cells to chemotherapy are required. Here, we screen the lysyl-oxidase (LOX) family to clarify its contribution to chemotherapy resistance in liver cancer. LOXL3 depletion significantly sensitizes liver cancer cells to Oxaliplatin by inducing ferroptosis. Chemotherapy-activated EGFR signaling drives LOXL3 to interact with TOM20, causing it to be hijacked into mitochondria, where LOXL3 lysyl-oxidase activity is reinforced by phosphorylation at S704. Metabolic adenylate kinase 2 (AK2) directly phosphorylates LOXL3-S704. Phosphorylated LOXL3-S704 targets dihydroorotate dehydrogenase (DHODH) and stabilizes it by preventing its ubiquitin-mediated proteasomal degradation. K344-deubiquitinated DHODH accumulates in mitochondria, in turn inhibiting chemotherapy-induced mitochondrial ferroptosis. CRISPR-Cas9-mediated site-mutation of mouse LOXL3-S704 to D704 causes a reduction in lipid peroxidation. Using an advanced liver cancer mouse model, we further reveal that low-dose Oxaliplatin in combination with the DHODH-inhibitor Leflunomide effectively inhibit liver cancer progression by inducing ferroptosis, with increased chemotherapy sensitivity and decreased chemotherapy toxicity.

Suggested Citation

  • Meixiao Zhan & Yufeng Ding & Shanzhou Huang & Yuhang Liu & Jing Xiao & Hua Yu & Ligong Lu & Xiongjun Wang, 2023. "Lysyl oxidase-like 3 restrains mitochondrial ferroptosis to promote liver cancer chemoresistance by stabilizing dihydroorotate dehydrogenase," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38753-6
    DOI: 10.1038/s41467-023-38753-6
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    Cited by:

    1. Hui Yang & Qingqing Li & Xingxing Chen & Mingzhe Weng & Yakai Huang & Qiwen Chen & Xiaocen Liu & Haoyu Huang & Yanhuizhi Feng & Hanyu Zhou & Mengying Zhang & Weiya Pei & Xueqin Li & Qingsheng Fu & Lia, 2024. "Targeting SOX13 inhibits assembly of respiratory chain supercomplexes to overcome ferroptosis resistance in gastric cancer," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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