Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
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.
Nat Commun. 2019 Nov 6;10(1):5043. doi: 10.1038/s41467-019-12925-9.
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.
异常的癌症抗氧化能力被认为是肿瘤恶性的潜在机制。调节氧化应激状态正成为一种抗癌治疗方法。我们之前的研究发现，巢蛋白敲低的细胞在非小细胞肺癌（NSCLC）中对氧化应激更敏感。然而，巢蛋白保护细胞免受氧化损伤的分子机制尚不清楚。在这里，我们确定了巢蛋白和 Nrf2 之间的反馈环，以维持氧化还原平衡。从机制上讲，巢蛋白的 ESGE 基序与 Keap1 的 Kelch 结构域相互作用，并与 Nrf2 竞争与 Keap1 的结合，导致 Nrf2 逃避 Keap1 介导的降解，进而促进抗氧化酶的产生。有趣的是，我们还发现巢蛋白启动子中的抗氧化反应元件（AREs）通过 Nrf2 负责其诱导。总之，我们的结果表明，巢蛋白-Keap1-Nrf2 轴调节细胞内氧化还原平衡，并赋予 NSCLC 对氧化应激的抗性。
