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

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 Zhang, Xin Pan, Yue-yin Pan, Ping Gao, Huafeng Zhang, Cong-zhao Zhou, Jing Guo () and Zhenye Yang ()
Additional contact information
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

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13485-8

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