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LKB1 reduces ROS-mediated cell damage via activation of p38

Oncogene volume 34, pages 3848–3859 (2015)Cite this article

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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.

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Acknowledgements

We thank Dr Mousseau at University of Saskatchewan for providing p38-WT, CA and DN constructs; Dr Laderoute at SRI International for providing WT and AMPK-null MEFs; Dr Frazier at University of Texas MD Cancer Center for providing the LKB1-null cells; Dr Lizhong Wang from University of Alabama at Birmingham for providing WT and LKB1fl/fl MEFs. This work was supported by grants from National Cancer Institute R01CA133053 (ZXX) and the National 863 Program #2004AA205020 and the National Natural Science Foundation of China #30700872 (YLL).

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  1. H-G Xu

    Present address: 6Current address: Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.,

Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA

    H-G Xu, J Chen, R-X Zhao, X Xiao, Q He, K D Werle, H-G Kim, R Lopez & Z-X Xu

  2. Department of Pathology, Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China

    Y-X Zhai, J-W Wang, C-S Quan, Y-L Li & Z-X Xu

  3. Department of Endocrinology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Y Lu

  4. Department of Dermatology, Boston University, School of Medicine, Boston, MA, USA

    R Cui

  5. Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX, USA

    J Liang

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Xu, HG., Zhai, YX., Chen, J. et al. LKB1 reduces ROS-mediated cell damage via activation of p38. Oncogene 34, 3848–3859 (2015). https://doi.org/10.1038/onc.2014.315

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