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Keap1-Nrf2 Interaction Suppresses Cell Motility in Lung Adenocarcinomas by Targeting the S100P Protein

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 contribu...

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Published in:Clinical cancer research 2015-10, Vol.21 (20), p.4719-4732
Main Authors: Chien, Ming-Hsien, Lee, Wei-Jiunn, Hsieh, Feng-Koo, Li, Chia-Feng, Cheng, Tsu-Yao, Wang, Ming-Yang, Chen, Jin-Shing, Chow, Jyh-Ming, Jan, Yi-Hua, Hsiao, Michael, Hua, Kuo-Tai, Kuo, Min-Liang
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cited_by cdi_FETCH-LOGICAL-c507t-29b2dca4d2ecc69365ea75bb86a2600e55eae1203add7a0bcefffc4663422ff03
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container_title Clinical cancer research
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creator Chien, Ming-Hsien
Lee, Wei-Jiunn
Hsieh, Feng-Koo
Li, Chia-Feng
Cheng, Tsu-Yao
Wang, Ming-Yang
Chen, Jin-Shing
Chow, Jyh-Ming
Jan, Yi-Hua
Hsiao, Michael
Hua, Kuo-Tai
Kuo, Min-Liang
description 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). 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. 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. 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.
doi_str_mv 10.1158/1078-0432.ccr-14-2880
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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). 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. 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. 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source Freely Accessible Science Journals - check A-Z of ejournals
subjects Adenocarcinoma - metabolism
Adenocarcinoma - pathology
Adenocarcinoma of Lung
Calcium-Binding Proteins - metabolism
Carcinoma, Non-Small-Cell Lung - metabolism
Carcinoma, Non-Small-Cell Lung - pathology
Cell Line, Tumor
Cell Movement - physiology
Female
Gene Expression Regulation, Neoplastic - physiology
HCT116 Cells
Humans
Intracellular Signaling Peptides and Proteins - metabolism
Kelch-Like ECH-Associated Protein 1
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
Male
MCF-7 Cells
Middle Aged
Neoplasm Proteins - metabolism
NF-E2-Related Factor 2 - metabolism
Oxidative Stress - physiology
Signal Transduction - physiology
title Keap1-Nrf2 Interaction Suppresses Cell Motility in Lung Adenocarcinomas by Targeting the S100P Protein
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