Ren Yi, Chen Jiaqing, Chen Peishi, Hao Qi, Cheong Leng-Kuan, Tang Mingzhu, Hong Lian-Lian, Hu Xuan-Yu, Bay Boon-Huat, Ling Zhi-Qiang, Shen Han-Ming
Faculty of Health Sciences, University of Macau, Taipa, Macau, China; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Free Radic Biol Med. 2021 Apr;166:128-139. doi: 10.1016/j.freeradbiomed.2021.02.018. Epub 2021 Feb 23.
The liver kinase B1 (LKB1) is an important tumor suppressor and its loss-of-function mutations are observed in around 16% of non-small cell lung cancer (NSCLC) cases. One of the main functions of LKB1 is to activate AMP-activated protein kinase (AMPK) via direct phosphorylation. Under metabolic or energy stress conditions, the LKB1-AMPK axis inhibits the anabolic pathways and activates the catabolic pathways to maintain metabolic homeostasis for cell survival. In this study, we found that LKB1-mutant NSCLC cells are particularly susceptible to cell death induced by glucose starvation, but not by other forms of starvation such as amino acid starvation or serum starvation. Reconstitution of LKB1 in LKB1-mutant cells or LKB1 knockout in LKB1-wild type cells highlighted the importance of the LKB1-AMPK axis for cell survival under glucose starvation. Mechanistically, in LKB1-mutant cells, glucose starvation elicits oxidative stress, which causes AMPK protein oxidation and inactivation, and eventually cell death. Importantly, this process could be effectively reversed and rescued by 2DG (a glucose analog capable of producing NADPH, a key antioxidant), A769662 (an allosteric AMPK activator), and N-acetyl cysteine (NAC) (a ROS scavenger), indicating the presence of a vicious circle between AMPK inactivation and ROS in LKB1-mutant NSCLC cells under glucose starvation. Our study thus elucidates the critical role of redox balance in determining the susceptibility to cell death under glucose starvation in LKB1-mutant NSCLC cells. The findings from this study reveal important clues in search of novel therapeutic strategies for LKB1-mutant NSCLC by targeting glucose metabolism and redox balance.
肝脏激酶B1（LKB1）是一种重要的肿瘤抑制因子，在约16%的非小细胞肺癌（NSCLC）病例中观察到其功能丧失突变。LKB1的主要功能之一是通过直接磷酸化激活AMP激活的蛋白激酶（AMPK）。在代谢或能量应激条件下，LKB1-AMPK轴抑制合成代谢途径并激活分解代谢途径，以维持细胞存活的代谢稳态。在本研究中，我们发现LKB1突变的NSCLC细胞对葡萄糖饥饿诱导的细胞死亡特别敏感，但对其他形式的饥饿如氨基酸饥饿或血清饥饿不敏感。在LKB1突变细胞中重建LKB1或在LKB1野生型细胞中敲除LKB1突出了LKB1-AMPK轴在葡萄糖饥饿下对细胞存活的重要性。从机制上讲，在LKB1突变细胞中，葡萄糖饥饿引发氧化应激，导致AMPK蛋白氧化和失活，最终导致细胞死亡。重要的是，这一过程可以被2DG（一种能够产生关键抗氧化剂NADPH的葡萄糖类似物）、A769662（一种变构AMPK激活剂）和N-乙酰半胱氨酸（NAC）（一种ROS清除剂）有效逆转和挽救，表明在葡萄糖饥饿下LKB1突变的NSCLC细胞中AMPK失活和ROS之间存在恶性循环。因此，我们的研究阐明了氧化还原平衡在决定LKB1突变的NSCLC细胞在葡萄糖饥饿下对细胞死亡易感性方面的关键作用。本研究的结果揭示了通过靶向葡萄糖代谢和氧化还原平衡寻找LKB1突变NSCLC新治疗策略的重要线索。
