Nestin regulates cellular redox homeostasis in lung cancer through the Keap1–Nrf2 feedback loop
| Autor: | Yuanyuan Wang, Jiancheng Wang, Xiaofan Lai, Qiying Lu, Yue Shi, Maosheng Wang, Kang Zhang, Qiong Ke, Yi Wang, Yinong Huang, Andy Peng Xiang, Yuan Qiu, Yuanjun Guan, Jianye Cai, Xin Liu, Hao-Xiang Wu, Yanan Zhang |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Lung Neoplasms Ubiquitylation Cell General Physics and Astronomy Apoptosis medicine.disease_cause environment and public health Antioxidants Nestin Mice 0302 clinical medicine Carcinoma Non-Small-Cell Lung Homeostasis Intermediate filaments lcsh:Science Mice Inbred BALB C Kelch-Like ECH-Associated Protein 1 Multidisciplinary Chemistry Intracellular Signaling Peptides and Proteins respiratory system Cell biology medicine.anatomical_structure Gene Knockdown Techniques 030220 oncology & carcinogenesis Cell Survival NF-E2-Related Factor 2 Science Mice Nude macromolecular substances digestive system Article General Biochemistry Genetics and Molecular Biology Stress signalling 03 medical and health sciences Cell Line Tumor medicine Animals Humans Antioxidant Response Elements A549 cell HEK 293 cells Ubiquitination General Chemistry KEAP1 Oxidative Stress HEK293 Cells 030104 developmental biology nervous system A549 Cells lcsh:Q Non-small-cell lung cancer Oxidative stress |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-17 (2019) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. Loss of Nestin sensitizes non-small cell lung carcinoma (NSCLC) to oxidative stress. Here, the authors report a feedback loop between Nestin and Nrf2 wherein Nestin competes with Nrf2 for Keap1 binding, preventing Nrf2 degradation, and show the Nestin–Keap1–Nrf2 axis to regulate redox homeostasis in NSCLC. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|