Document Detail

FOXO3a elicits a pro-apoptotic transcription program and cellular response to human lung carcinogen nicotine-derived nitrosaminoketone (NNK).
MedLine Citation:
PMID:  19380174     Owner:  NLM     Status:  MEDLINE    
Long-term carcinogen exposure exerts continuous pressure on key mechanisms that repair or eliminate carcinogen-damaged cells giving rise to selective failures that contribute to lung cancer. FOXO3a is a transcription factor that elicits a protective response to diverse cellular stresses. Although implicated as a tumor suppressor, its role in sporadic cancer is uncertain. We recently observed that FOXO3a gene inactivation occurs frequently in carcinogen-induced lung adenocarcinoma (LAC). This suggests that FOXO3a may play a role in LAC suppression by eliciting a protective response to carcinogenic stress. Here we investigated this possibility by examining the role of FOXO3a in the cellular response to nicotine-derived nitrosaminoketone (NNK), a lung carcinogen implicated as a cause of human LAC. We show that restoration of FOXO3a in FOXO3a-deficient LAC cells increases sensitivity to apoptosis caused by a DNA-damaging intermediate of NNK. Prior to this cellular outcome, FOXO3a is functionally activated and mediates a large-scale transcription program in response to this damage involving a significant modulation of 440 genes. Genes most significantly represented in this program are those with roles in cell growth and proliferation>protein synthesis>gene expression>cell death>cell cycle. The results of this study show that FOXO3a directs an anti-carcinogenic transcription program that culminates in the elimination of carcinogen-damaged cells. This suggests that FOXO3a is a potential suppressor of carcinogenic damage in LAC.
Daniel C Blake; Oliver R Mikse; Willard M Freeman; Christopher R Herzog
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Lung cancer (Amsterdam, Netherlands)     Volume:  67     ISSN:  1872-8332     ISO Abbreviation:  Lung Cancer     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2009-12-16     Completed Date:  2010-02-23     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8800805     Medline TA:  Lung Cancer     Country:  Ireland    
Other Details:
Languages:  eng     Pagination:  37-47     Citation Subset:  IM    
Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, USA.
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MeSH Terms
Adenocarcinoma / chemically induced*,  genetics
Apoptosis / genetics*
Carcinogens / toxicity*
Cell Line, Tumor
Forkhead Transcription Factors / genetics,  metabolism*
Gene Expression Regulation, Neoplastic*
Lung Neoplasms / chemically induced*,  genetics
Nicotine / chemistry,  toxicity*
Nitrosamines / toxicity*
Transcription, Genetic
Tumor Suppressor Proteins / genetics,  metabolism*
Reg. No./Substance:
0/Carcinogens; 0/FOXO3 protein, human; 0/Forkhead Transcription Factors; 0/Nitrosamines; 0/Tumor Suppressor Proteins; 54-11-5/Nicotine; 64091-91-4/4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone

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