title: LKB1 reduces ROS-mediated cell damage via activation of p38.
abstract: 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.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: H-G
authors.initials: HG
authors.lastname: Xu
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, Norman Bethune College of Medicine, Jilin University, Changchun, China.
authors.forename: Y-X
authors.initials: YX
authors.lastname: Zhai
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Endocrinology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, Norman Bethune College of Medicine, Jilin University, Changchun, China.
authors.forename: J-W
authors.initials: JW
authors.lastname: Wang
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, Norman Bethune College of Medicine, Jilin University, Changchun, China.
authors.forename: C-S
authors.initials: CS
authors.lastname: Quan
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: R-X
authors.initials: RX
authors.lastname: Zhao
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: X
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: He
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: K D
authors.initials: KD
authors.lastname: Werle
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: H-G
authors.initials: HG
authors.lastname: Kim
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: R
authors.initials: R
authors.lastname: Lopez
authors.affiliation: Department of Dermatology, Boston University, School of Medicine, Boston, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Cui
authors.affiliation: Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Liang
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, Norman Bethune College of Medicine, Jilin University, Changchun, China.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Li
authors.affiliation: 1] Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA [2] Key Laboratory of Pathobiology, Ministry of Education, Department of Pathology, Norman Bethune College of Medicine, Jilin University, Changchun, China.
authors.forename: Z-X
authors.initials: ZX
authors.lastname: Xu
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000111:Acetylcysteine / Q000494:pharmacology; D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002374:Catalase / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004249:DNA Damage; D004622:Embryo, Mammalian / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099156:Superoxide Dismutase 2
chemical_list: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000111:Acetylcysteine; D051698:Activating Transcription Factor 2; D002374:Catalase; D016166:Free Radical Scavengers; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D020764:cdc42 GTP-Binding Protein; D054462:p21-Activated Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000099156:Superoxide Dismutase 2; C109790:STK11 protein, human; C491654:Stk11 protein, mouse