Keap1-Nrf2 interaction suppresses cell motility in lung adenocarcinomas by targeting the S100P protein
Journal
Clinical Cancer Research
Journal Volume
21
Journal Issue
20
Pages
4719-4732
Date Issued
2015
Author(s)
Chien M.-H.
Lee W.-J.
Hsieh F.-K.
Li C.-F.
Wang M.-Y.
Chow J.-M.
Jan Y.-H.
Hsiao M.
Kuo M.-L.
Abstract
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. ? 2015 AACR.
SDGs
Other Subjects
ezrin; kelch like ECH associated protein 1; membrane protein; protein S100P; transcription factor Nrf2; unclassified drug; calcium binding protein; KEAP1 protein, human; NFE2L2 protein, human; S100P protein, human; signal peptide; transcription factor Nrf2; tumor protein; Article; cancer growth; cancer survival; cell motility; cohort analysis; controlled study; correlation analysis; cytoskeleton; down regulation; human; human cell; human tissue; immunofluorescence microscopy; immunohistochemistry; lung adenocarcinoma; lymph node metastasis; major clinical study; non small cell lung cancer; priority journal; protein analysis; protein depletion; protein expression; protein function; protein protein interaction; protein targeting; real time polymerase chain reaction; survival rate; Western blotting; adenocarcinoma; cell motion; female; gene expression regulation; HCT116 cell line; lung tumor; male; MCF 7 cell line; metabolism; middle aged; non small cell lung cancer; oxidative stress; pathology; physiology; signal transduction; tumor cell line; Adenocarcinoma; Calcium-Binding Proteins; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Female; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Intracellular Signaling Peptides and Proteins; Lung Neoplasms; Male; MCF-7 Cells; Middle Aged; Neoplasm Proteins; NF-E2-Related Factor 2; Oxidative Stress; Signal Transduction
Publisher
American Association for Cancer Research Inc.
Type
journal article