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

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 5043 (11 06 2019) ISSN: 2041-1723 [Electronic] England
• PMID: 31695040 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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