| RRC ID |
43632
|
| 著者 |
Yamadori T, Ishii Y, Homma S, Morishima Y, Kurishima K, Itoh K, Yamamoto M, Minami Y, Noguchi M, Hizawa N.
|
| タイトル |
Molecular mechanisms for the regulation of Nrf2-mediated cell proliferation in non-small-cell lung cancers.
|
| ジャーナル |
Oncogene
|
| 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.
|
| 巻・号 |
31(45)
|
| ページ |
4768-77
|
| 公開日 |
2012-11-8
|
| DOI |
10.1038/onc.2011.628
|
| PII |
onc2011628
|
| PMID |
22249257
|
| MeSH |
Carcinoma, Non-Small-Cell Lung / genetics*
Carcinoma, Non-Small-Cell Lung / metabolism*
Cell Line, Tumor
Cell Proliferation
Drug Resistance, Neoplasm / genetics
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / genetics
ErbB Receptors / metabolism
Gene Expression Regulation, Neoplastic
Gene Silencing
Humans
Intracellular Signaling Peptides and Proteins / genetics
Kelch-Like ECH-Associated Protein 1
Ligands
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism*
Mitogen-Activated Protein Kinases / metabolism
Models, Biological
Mutation
NF-E2-Related Factor 2 / genetics*
NF-E2-Related Factor 2 / metabolism*
Oxidative Stress
Protein Kinase Inhibitors / pharmacology
Signal Transduction
|
| IF |
7.971
|
| 引用数 |
98
|
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
ONCOLOGY
GENETICS & HEREDITY
CELL BIOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
A549(RCB0098) |
