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.
Highlights
Abnormal cancer antioxidant capacity is considered as a potential mechanism of tumor malignancy
To explore whether Nestin influenced antioxidant capacity of these cells, we examined the gene expression levels of various antioxidant proteins, such as catalase (CAT), glutathione peroxidase 1 (GPX1), glutathione peroxidase 4 (GPX4), superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2), glutamate-cysteine ligase, catalytic subunit (GCLC), glutamate-cysteine ligase modifier subunit (GCLM), heme oxygenase 1 (HMOX-1), and NAD(P)H:quinone oxidoreductase 1 (NQO1)
As intracellular protein levels are determined by the balance between protein synthesis and degradation, we examined these parameters of Nrf[2] in non-small cell lung cancer (NSCLC) cells with or without Nestin knockdown. qPCR analysis revealed that Nestin knockdown had no effect on the transcription of Nrf[2] in NSCLC cells (Fig. 3a), prompting us to speculate that Nestin knockdown might impact the degradation of Nrf[2]
Summary
Abnormal cancer antioxidant capacity is considered as a potential mechanism of tumor malignancy. Our previous studies have found that Nestin-knockdown cells were more sensitive to oxidative stress in non-small cell lung cancer (NSCLC). Our results indicate that the Nestin–Keap1–Nrf[2] axis regulates cellular redox homeostasis and confers oxidative stress resistance in NSCLC. It is well known that an imbalance between reactive oxygen species (ROS) generation and elimination contributes to the moderate oxidative stress commonly seen in cancer[1]. Cancer cells characteristically have higher ROS levels than normal cells due to mitochondrial dysfunction or metabolic abnormality[2,3], and develop powerful antioxidant defenses that modulate. E2-related factor 2 (Nrf2), is considered to be a master regulator of the expression levels of various antioxidant enzymes, including glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1 (NQO1), and others, via binding enhancer sequences termed “antioxidant-response elements” (AREs)[5,6]. It has been demonstrated that the constitutive stabilization and activation of
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