PMID- 22249257
OWN - NLM
STAT- MEDLINE
DCOM- 20130116
LR  - 20181202
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 31
IP  - 45
DP  - 2012 Nov 8
TI  - Molecular mechanisms for the regulation of Nrf2-mediated cell proliferation in 
      non-small-cell lung cancers.
PG  - 4768-77
LID - 10.1038/onc.2011.628 [doi]
AB  - 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.
FAU - Yamadori, T
AU  - Yamadori T
AD  - Department of Respiratory Medicine, Institute of Clinical Medicine, University of 
      Tsukuba, Tsukuba, Ibaraki, Japan.
FAU - Ishii, Y
AU  - Ishii Y
FAU - Homma, S
AU  - Homma S
FAU - Morishima, Y
AU  - Morishima Y
FAU - Kurishima, K
AU  - Kurishima K
FAU - Itoh, K
AU  - Itoh K
FAU - Yamamoto, M
AU  - Yamamoto M
FAU - Minami, Y
AU  - Minami Y
FAU - Noguchi, M
AU  - Noguchi M
FAU - Hizawa, N
AU  - Hizawa N
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120116
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (KEAP1 protein, human)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (Ligands)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Carcinoma, Non-Small-Cell Lung/*genetics/*metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Drug Resistance, Neoplasm/genetics
MH  - ErbB Receptors/antagonists & inhibitors/genetics/metabolism
MH  - Gene Expression Regulation, Neoplastic
MH  - Gene Silencing
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/genetics
MH  - Kelch-Like ECH-Associated Protein 1
MH  - Ligands
MH  - Lung Neoplasms/*genetics/*metabolism
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Models, Biological
MH  - Mutation
MH  - NF-E2-Related Factor 2/*genetics/*metabolism
MH  - Oxidative Stress
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Signal Transduction
EDAT- 2012/01/18 06:00
MHDA- 2013/01/17 06:00
CRDT- 2012/01/18 06:00
PHST- 2012/01/18 06:00 [entrez]
PHST- 2012/01/18 06:00 [pubmed]
PHST- 2013/01/17 06:00 [medline]
AID - onc2011628 [pii]
AID - 10.1038/onc.2011.628 [doi]
PST - ppublish
SO  - Oncogene. 2012 Nov 8;31(45):4768-77. doi: 10.1038/onc.2011.628. Epub 2012 Jan 16.