Molecular mechanisms for the regulation of Nrf2-mediated cell proliferation in non-small-cell lung cancers
Open Access
- 16 January 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 31 (45), 4768-4777
- https://doi.org/10.1038/onc.2011.628
Abstract
We previously demonstrated that the transcription factor NF-E2-related factor2 (Nrf2), expressed abundantly in non-small-cell lung cancer (NSCLC) cells, plays a pivotal role in the proliferation and chemoresistance of NSCLC. Here we show that Nrf2-mediated NSCLC cell proliferation is dually regulated by epidermal growth factor receptor (EGFR) signaling and an Nrf2 repressor protein Keap1 (Kelch-like ECH-associated protein-1). NSCLC cells expressing wild-type EGFR and Keap1 genes show enhanced proliferation on stimulation with EGFR ligand under non-stress conditions. Exposure to cigarette smoke extract (CSE) enhanced cell proliferation by modification of the Nrf2/Keap1 interaction. Although EGFR-tyrosine kinase inhibitor (TKI) inhibited the proliferation of these cells, exposure to CSE attenuated its efficacy. In NSCLC cells with Keap1 gene mutations, Nrf2 was constitutively activated owing to dysfunction of Keap1 and cells proliferated independently of EGFR signaling. Furthermore, EGFR-TKI was unable to inhibit their proliferation. In NSCLC cells with EGFR gene mutations, Nrf2 was constitutively activated by EGFR signaling. In these cells, proliferation was largely dependent on the EGFR signaling pathway. Although these cells were highly sensitive to EGFR-TKI, exposure to CSE or knockdown of Keap1 mRNA reduced sensitivity to EGFR-TKI. We found a case of NSCLC showing resistance to EGFR-TKI despite having EGFR-TKI-sensitive EGFR gene mutation because of dysfunctional mutation in Keap1 gene. Results indicate that oxidative stress reduces the anticancer effects of EGFR-TKI in wild-type Keap1 NSCLC cells. Analysis of Keap1 dysfunction may become a novel molecular marker to predict resistance to EGFR-TKI in NSCLC cells having EGFR-TKI-sensitive EGFR mutations. Finally, as the downstream molecule of both EGFR and Keap1 signaling, Nrf2 is an important molecular target for the treatment of NSCLC, where cells have mutations in EGFR, KRAS or Keap1 genes.Keywords
This publication has 32 references indexed in Scilit:
- Nrf2 and Keap1 Abnormalities in Non–Small Cell Lung Carcinoma and Association with Clinicopathologic FeaturesClinical Cancer Research, 2010
- Up-regulation of Nrf2-mediated heme oxygenase-1 expression by eckol, a phlorotannin compound, through activation of Erk and PI3K/AktThe International Journal of Biochemistry & Cell Biology, 2010
- Nrf2 Enhances Cell Proliferation and Resistance to Anticancer Drugs in Human Lung CancerClinical Cancer Research, 2009
- RNAi-Mediated Silencing of Nuclear Factor Erythroid-2–Related Factor 2 Gene Expression in Non–Small Cell Lung Cancer Inhibits Tumor Growth and Increases Efficacy of ChemotherapyCancer Research, 2008
- Loss of Keap1 Function Activates Nrf2 and Provides Advantages for Lung Cancer Cell GrowthCancer Research, 2008
- Annual report to the nation on the status of cancer, 1975–2004, featuring cancer in American Indians and Alaska NativesCancer, 2007
- The Epidermal Growth Factor Receptor Pathway: A Model for Targeted TherapyClinical Cancer Research, 2006
- Mechanistic Studies of the Nrf2-Keap1 Signaling PathwayDrug Metabolism Reviews, 2006
- Keap1 Is a Redox-Regulated Substrate Adaptor Protein for a Cul3-Dependent Ubiquitin Ligase ComplexMolecular and Cellular Biology, 2004
- Oxidative Stress Sensor Keap1 Functions as an Adaptor for Cul3-Based E3 Ligase To Regulate Proteasomal Degradation of Nrf2Molecular and Cellular Biology, 2004