Key Laboratory of Laboratory Medical Diagnostics Designed by Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
Experimental Teaching Center of Basic Medicine Science, Chongqing Medical University, Chongqing, 400016, China.
Cell Death Dis. 2019 Mar 8;10(3):228. doi: 10.1038/s41419-019-1475-7.
Citrate, a substance being related to de novo fatty acid synthesis and tricarboxylic acid (TCA) cycle, has a pivotal role in cell survival. However, the molecular mechanisms that regulate intracellular citrate in triple-negative breast cancer (TNBC), especially under hypoxic condition, remain poorly understood. Here we find that hypoxia (1% O) induces DNA damage-independent ATM activation (oxidized ATM) and suppression of oxidized ATM reduces intracellular citrate via decreasing the levels of phosphofructokinase (PFKP) and citrate synthase (CS), two key glucose metabolism-associated enzymes. Mechanistically, PFKP is regulated by HIF1A at the translational level, whereas CS is of posttranscriptional regulation by UBR5-mediated ubiquitination. Interestingly, accumulation of citrate in cytoplasm or exogenous citrate significantly enhances cell migration, invasion, and metastasis of hypoxic TNBC cells in vitro and in mice xenografts. The underlying mechanism mainly involves citrate-stimulated activation of the AKT/ERK/MMP2/9 signaling axis. Our findings unravel a novel function of oxidized ATM in promoting migration, invasion, and metastasis of TNBC.
柠檬酸是一种与从头脂肪酸合成和三羧酸（TCA）循环有关的物质，在细胞存活中起着关键作用。然而，调节三阴性乳腺癌（TNBC）细胞内柠檬酸的分子机制，特别是在缺氧条件下，仍知之甚少。在这里，我们发现缺氧（1% O）诱导 DNA 损伤非依赖性 ATM 激活（氧化 ATM），并且抑制氧化 ATM 通过降低磷酸果糖激酶（PFKP）和柠檬酸合酶（CS）的水平来减少细胞内柠檬酸，PFKP 和 CS 是两种与葡萄糖代谢相关的关键酶。从机制上讲，PFKP 在翻译水平上受到 HIF1A 的调节，而 CS 则通过 UBR5 介导的泛素化进行转录后调节。有趣的是，细胞质中柠檬酸的积累或外源性柠檬酸显著增强了缺氧 TNBC 细胞在体外和小鼠异种移植物中的迁移、侵袭和转移。潜在的机制主要涉及柠檬酸刺激 AKT/ERK/MMP2/9 信号轴的激活。我们的研究结果揭示了氧化 ATM 在促进 TNBC 迁移、侵袭和转移中的新功能。
