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

• Published in: Nature communications Vol. 10; no. 1; pp. 5566 - 16
• Main Authors: Cheng, Aoxing, Zhang, Peng, Wang, Bo, Yang, Dongdong, Duan, Xiaotao, Jiang, Yongliang, Xu, Tian, Jiang, Ya, Shi, Jiahui, Ding, Chengtao, Wu, Gao, Sang, Zhihong, Wu, Qiang, Wang, Hua, Wu, Mian, Zhang, Zhiyong, Pan, Xin, Pan, Yue-yin, Gao, Ping, Zhang, Huafeng, Zhou, Cong-zhao, Guo, Jing, Yang, Zhenye
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05-12-2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 14/33; 631/67/2327; 631/67/395; 82/16; 82/58; 82/80; 96/10; Animals; Aurora Kinase A - antagonists & inhibitors; Aurora Kinase A - metabolism; Azepines - pharmacology; Cancer; Cell culture; Cell Line, Tumor; Glycolysis; HEK293 Cells; HeLa Cells; Humanities and Social Sciences; Humans; Intermediates; Isoenzymes - genetics; Isoenzymes - metabolism; Kinases; L-Lactate dehydrogenase; L-Lactate Dehydrogenase - genetics; L-Lactate Dehydrogenase - metabolism; Lactate dehydrogenase; Lactic acid; Lactic Acid - metabolism; Male; Mice, Inbred BALB C; Mice, Nude; multidisciplinary; Mutation; NAD; NADH; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Nicotinamide adenine dinucleotide; Phosphorylation; Pyrimidines - pharmacology; Pyruvic acid; Pyruvic Acid - metabolism; Pyruvic Acid - pharmacology; Regeneration; Science; Science (multidisciplinary); Serine; Serine - genetics; Serine - metabolism; Substrate inhibition; Substrate Specificity - drug effects; Substrates; Tumor Burden - drug effects; Tumors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13485-8

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.
Aurora-A kinase is frequently over-expressed in tumours. Here, the authors show that it modulates the activity of lactate dehydrogenase B, resulting in enhanced glycolysis, bio-synthesis and tumour growth.