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Keap1-Nrf2 Interaction Suppresses Cell Motility in Lung Adenocarcinomas by Targeting the S100P Protein
Ming-Hsien Chien1, Wei-Jiunn Lee2, Feng-Koo Hsieh3
1Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
Purpose:
Kelch-like ECH-associated protein 1 (Keap1) is an E3 ligase participated in the cellular defense response against oxidative stress through nuclear factor erythroid-2-related factor 2 (Nrf2). However, the role of Keap1 in regulating cancer motility is still controversial. We investigated the contribution of the Keap1-Nrf2 axis in the progression of non-small cell lung cancer (NSCLC).
Experimental Design:
The expression of Keap1 and Nrf2 was examined via immunohistochemistry, real-time PCR, and Western blot analysis in a cohort of NSCLC tissues and cells. A series of in vivo and in vitro assays was performed to elucidate the contribution of the Keap1-Nrf2 axis in lung cancer mobility and progression.
Results:
Keap1 expression was decreased in specimens from NSCLC patients with lymph node metastasis compared with patients without metastasis. Higher Keap1 expression levels were correlated with the survival of NSCLC patients. Moreover, manipulation of Keap1 expression affected cell migration/invasion abilities. Depletion of Nrf2 relieved the migration promotion imposed by Keap1 suppression. Mechanistic investigations found that S100P was downregulated in both Keap1-overexpressing and Nrf2-knockdown NSCLC cells. Overexpression of Keap1 and knockdown of Nrf2 both suppressed S100P expression in NSCLC cells. Knockdown of S100P inhibited cell migration in highly invasive NSCLC cells and also relieved the migration promotion imposed by Keap1 suppression in weakly invasive NSCLC cells.
Conclusions:
Our findings suggest that Keap1 functions as a suppressor of tumor metastasis by targeting the Nrf2/S100P pathway in NSCLC cells. In addition, overexpression of Keap1 may be a novel NSCLC treatment strategy and/or useful biomarker for predicting NSCLC progression.
Insights
Kelch-like ECH-associated protein 1 (Keap1) suppresses non-small cell lung cancer (NSCLC) metastasis by targeting the Nrf2/S100P pathway. Increased Keap1 may serve as a biomarker or treatment strategy for NSCLC progression.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Biology
Background:
- Kelch-like ECH-associated protein 1 (Keap1) regulates cellular defense via the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway.
- The precise role of Keap1 in cancer cell motility remains debated.
- Understanding the Keap1-Nrf2 axis is crucial for non-small cell lung cancer (NSCLC) progression.
Purpose of the Study:
- To investigate the role of the Keap1-Nrf2 axis in non-small cell lung cancer (NSCLC) progression.
- To determine the contribution of Keap1 to cancer cell motility and metastasis.
Main Methods:
- Immunohistochemistry, real-time PCR, and Western blot analysis were used to assess Keap1 and Nrf2 expression in NSCLC tissues and cells.
- In vivo and in vitro assays were conducted to evaluate the impact of the Keap1-Nrf2 axis on lung cancer cell mobility.
- Mechanistic studies explored the downstream targets involved in Keap1-mediated regulation.
Main Results:
- Keap1 expression was lower in NSCLC patients with lymph node metastasis and correlated with patient survival.
- Keap1 suppression promoted NSCLC cell migration and invasion, an effect reversed by Nrf2 depletion.
- S100P was identified as a downstream target, downregulated by Keap1 overexpression or Nrf2 knockdown, and its inhibition suppressed cell migration.
Conclusions:
- Keap1 acts as a tumor metastasis suppressor in NSCLC by regulating the Nrf2/S100P pathway.
- Overexpression of Keap1 presents a potential therapeutic strategy and a predictive biomarker for NSCLC progression.
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