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Nature communications
11 06, 2019;10 (1): 5043.

Nestin regulates cellular redox homeostasis in lung cancer through the Keap1-Nrf2 feedback loop.

Jiancheng Wang, Qiying Lu, Jianye Cai, Yi Wang, Xiaofan Lai, Yuan Qiu, Yinong Huang, Qiong Ke, Yanan Zhang, Yuanjun Guan, Haoxiang Wu, Yuanyuan Wang, Xin Liu, Yue Shi, Kang Zhang, Maosheng Wang, Andy Peng Xiang
Author Information
  1. Jiancheng Wang: Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
  2. Qiying Lu: Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
  3. Jianye Cai: Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China.
  4. Yi Wang: Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
  5. Xiaofan Lai: Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  6. Yuan Qiu: Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
  7. Yinong Huang: Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China.
  8. Qiong Ke: Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
  9. Yanan Zhang: Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
  10. Yuanjun Guan: Core Facility of Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
  11. Haoxiang Wu: Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China.
  12. Yuanyuan Wang: Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China. ORCID
  13. Xin Liu: Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China.
  14. Yue Shi: Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China.
  15. Kang Zhang: Faculty of Medicine, Macau University of Science and Technology, Macau, China.
  16. Maosheng Wang: The Cardiovascular Center, Gaozhou People's Hospital, Maoming, China. mmwmsmd@126.com.
  17. Andy Peng Xiang: Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China. xiangp@mail.sysu.edu.cn.
PMID: 31695040 DOI: 10.1038/s41467-019-12925-9

Abstract

Abnormal cancer antioxidant capacity is considered as a potential mechanism of tumor malignancy. Modulation of oxidative stress status is emerging as an anti-cancer treatment. Our previous studies have found that Nestin-knockdown cells were more sensitive to oxidative stress in non-small cell lung cancer (NSCLC). However, the molecular mechanism by which Nestin protects cells from oxidative damage remains unclear. Here, we identify a feedback loop between Nestin and Nrf2 maintaining the redox homeostasis. Mechanistically, the ESGE motif of Nestin interacts with the Kelch domain of Keap1 and competes with Nrf2 for Keap1 binding, leading to Nrf2 escaping from Keap1-mediated degradation, subsequently promoting antioxidant enzyme generation. Interestingly, we also map that the antioxidant response elements (AREs) in the Nestin promoter are responsible for its induction via Nrf2. Taken together, our results indicate that the Nestin-Keap1-Nrf2 axis regulates cellular redox homeostasis and confers oxidative stress resistance in NSCLC.

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MeSH Term

A549 Cells
Animals
Antioxidant Response Elements
Antioxidants
Apoptosis
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
Cell Survival
Gene Knockdown Techniques
HEK293 Cells
Homeostasis
Humans
Intracellular Signaling Peptides and Proteins
Kelch-Like ECH-Associated Protein 1
Lung Neoplasms
Male
Mice
Mice, Inbred BALB C
Mice, Nude
NF-E2-Related Factor 2
Nestin
Oxidative Stress
Ubiquitination

Chemicals

Antioxidants
Intracellular Signaling Peptides and Proteins
KEAP1 protein, human
Kelch-Like ECH-Associated Protein 1
NES protein, human
NF-E2-Related Factor 2
NFE2L2 protein, human
Nestin
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 10

Word Cloud

Created with Highcharts 10.0.0NestinoxidativeNrf2cancerantioxidantstressredoxhomeostasismechanismcellslungNSCLCfeedbackloopKeap1regulatescellularAbnormalcapacityconsideredpotentialtumormalignancyModulationstatusemerginganti-cancertreatmentpreviousstudiesfoundNestin-knockdownsensitivenon-smallcellHowevermolecularprotectsdamageremainsunclearidentifymaintainingMechanisticallyESGEmotifinteractsKelchdomaincompetesbindingleadingescapingKeap1-mediateddegradationsubsequentlypromotingenzymegenerationInterestinglyalsomapresponseelementsAREspromoterresponsibleinductionviaTakentogetherresultsindicatethe Nestin-Keap1-Nrf2axisconfersresistanceKeap1-Nrf2

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