Aurora-A mediated phosphorylation of LDHB promotes glycolysis and tumor progression by relieving the substrate-inhibition effect
Aurora-A mediated phosphorylation of LDHB promotes glycolysis and tumor progression by relieving the substrate-inhibition effect
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Aurora-A 介导的 LDHB 磷酸化通过减轻底物抑制作用来促进糖酵解和肿瘤进展。
DOI：
10.1038/s41467-019-13485-8
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发表时间：
2019-12-05
影响因子：
16.6
通讯作者：
Yang, Zhenye
中科院分区：
文献类型：
--
作者：
Cheng, Aoxing;Zhang, Peng;Yang, Zhenye
过表达的Aurora-A激酶通过多种途径促进肿瘤生长，但Aurora-A是否也参与代谢重编程介导的癌症进展尚不清楚。在这里，我们报告了Aurora-A直接与乳酸脱氢酶B(LDHB)相互作用并使其磷酸化，LDHB是四聚体酶LDH的一个亚单位，催化丙酮酸和乳酸之间的相互转化。Aurora-A介导的LDHB丝氨酸磷酸化显著提高了其将丙酮酸还原为乳酸的活性，从而有效地促进了NAD+的再生、糖酵解通量、乳酸的产生和与糖酵解中间体的生物合成。从机理上讲，LDHB丝氨酸162的磷酸化解除了丙酮酸对其底物的抑制作用，使丙酮酸和NADH转化为乳酸和NAD+的速率显著提高。通过表达LDHB-S162a突变体来阻断S162的磷酸化，抑制了癌细胞和异种移植模型中的糖酵解和肿瘤生长。这项研究揭示了Aurora-A在糖酵解调节中的作用以及LDHB直接促进Warburg效应的机制。
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.