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Aurora-A mediated phosphorylation of LDHB promotes glycolysis and tumor progression by relieving the substrate-inhibition effect

Author

Listed:
  • Aoxing Cheng

    (University of Science and Technology of China)

  • Peng Zhang

    (University of Science and Technology of China)

  • Bo Wang

    (Beijing Institute of Pharmacology and Toxicology)

  • Dongdong Yang

    (University of Science and Technology of China)

  • Xiaotao Duan

    (Beijing Institute of Pharmacology and Toxicology)

  • Yongliang Jiang

    (University of Science and Technology of China)

  • Tian Xu

    (University of Science and Technology of China)

  • Ya Jiang

    (University of Science and Technology of China)

  • Jiahui Shi

    (University of Science and Technology of China)

  • Chengtao Ding

    (University of Science and Technology of China)

  • Gao Wu

    (University of Science and Technology of China)

  • Zhihong Sang

    (National Center of Biomedical Analysis)

  • Qiang Wu

    (Anhui Medical University)

  • Hua Wang

    (the First Affiliated Hospital of Anhui Medical University)

  • Mian Wu

    (University of Science and Technology of China)

  • Zhiyong Zhang

    (University of Science and Technology of China)

  • Xin Pan

    (National Center of Biomedical Analysis)

  • Yue-yin Pan

    (University of Science and Technology of China)

  • Ping Gao

    (University of Science and Technology of China)

  • Huafeng Zhang

    (University of Science and Technology of China)

  • Cong-zhao Zhou

    (University of Science and Technology of China)

  • Jing Guo

    (University of Science and Technology of China)

  • Zhenye Yang

    (University of Science and Technology of China)

Abstract

Overexpressed Aurora-A kinase promotes tumor growth through various pathways, but whether Aurora-A is also involved in metabolic reprogramming-mediated cancer progression remains unknown. Here, we report that Aurora-A directly interacts with and phosphorylates lactate dehydrogenase B (LDHB), a subunit of the tetrameric enzyme LDH that catalyzes the interconversion between pyruvate and lactate. Aurora-A-mediated phosphorylation of LDHB serine 162 significantly increases its activity in reducing pyruvate to lactate, which efficiently promotes NAD+ regeneration, glycolytic flux, lactate production and bio-synthesis with glycolytic intermediates. Mechanistically, LDHB serine 162 phosphorylation relieves its substrate inhibition effect by pyruvate, resulting in remarkable elevation in the conversions of pyruvate and NADH to lactate and NAD+. Blocking S162 phosphorylation by expression of a LDHB-S162A mutant inhibited glycolysis and tumor growth in cancer cells and xenograft models. This study uncovers a function of Aurora-A in glycolytic modulation and a mechanism through which LDHB directly contributes to the Warburg effect.

Suggested Citation

  • Aoxing Cheng & Peng Zhang & Bo Wang & Dongdong Yang & Xiaotao Duan & Yongliang Jiang & Tian Xu & Ya Jiang & Jiahui Shi & Chengtao Ding & Gao Wu & Zhihong Sang & Qiang Wu & Hua Wang & Mian Wu & Zhiyong, 2019. "Aurora-A mediated phosphorylation of LDHB promotes glycolysis and tumor progression by relieving the substrate-inhibition effect," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13485-8
    DOI: 10.1038/s41467-019-13485-8
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