Xu H-G, Zhai Y-X, Chen J, Lu Y, Wang J-W, Quan C-S, Zhao R-X, Xiao X, He Q, Werle K D, Kim H-G, Lopez R, Cui R, Liang J, Li Y-L, Xu Z-X
Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, Norman Bethune College of Medicine, Jilin University, Changchun, China.
Oncogene. 2015 Jul;34(29):3848-59. doi: 10.1038/onc.2014.315. Epub 2014 Sep 29.
Liver kinase B1 (LKB1, also known as serine/threonine kinase 11, STK11) is a tumor suppressor mutated in Peutz-Jeghers syndrome and in a variety of sporadic cancers. Herein, we demonstrate that LKB1 controls the levels of intracellular reactive oxygen species (ROS) and protects the genome from oxidative damage. Cells lacking LKB1 exhibit markedly increased intracellular ROS levels, excessive oxidation of DNA, increased mutation rates and accumulation of DNA damage, which are effectively prevented by ectopic expression of LKB1 and by incubation with antioxidant N-acetylcysteine. The role of LKB1 in suppressing ROS is independent of AMP-activated protein kinase, a canonical substrate of LKB1. Instead, under the elevated ROS, LKB1 binds to and maintains the activity of the cdc42-PAK1 (p21-activated kinase 1) complex, which triggers the activation of p38 and its downstream signaling targets, such as ATF-2, thereby enhancing the activity of superoxide dismutase-2 and catalase, two antioxidant enzymes that protect the cells from ROS accumulation, DNA damage and loss of viability. Our results provide a new paradigm for a non-canonical tumor suppressor function of LKB1 and highlight the importance of targeting ROS signaling as a potential therapeutic strategy for cancer cells lacking LKB1.
肝脏激酶B1（LKB1，也称为丝氨酸/苏氨酸激酶11，STK11）是一种在黑斑息肉综合征和多种散发性癌症中发生突变的肿瘤抑制因子。在此，我们证明LKB1可控制细胞内活性氧（ROS）水平，并保护基因组免受氧化损伤。缺乏LKB1的细胞表现出细胞内ROS水平显著升高、DNA过度氧化、突变率增加以及DNA损伤积累，而LKB1的异位表达和与抗氧化剂N-乙酰半胱氨酸孵育可有效预防这些情况。LKB1在抑制ROS方面的作用独立于其典型底物AMP激活的蛋白激酶。相反，在ROS升高的情况下，LKB1与cdc42-PAK1（p21激活激酶1）复合物结合并维持其活性，该复合物触发p38及其下游信号靶点（如ATF-2）的激活，从而增强超氧化物歧化酶-2和过氧化氢酶的活性，这两种抗氧化酶可保护细胞免受ROS积累、DNA损伤和活力丧失的影响。我们的结果为LKB1的非典型肿瘤抑制功能提供了新的范例，并强调了靶向ROS信号作为缺乏LKB1的癌细胞潜在治疗策略的重要性。
