Document Detail

Effects of chronic nicotine on the autocrine regulation of pancreatic cancer cells and pancreatic duct epithelial cells by stimulatory and inhibitory neurotransmitters.
MedLine Citation:
PMID:  22791813     Owner:  NLM     Status:  MEDLINE    
Pancreatic ductal adenocarcinoma (PDAC) has a mortality rate near 100%. Smoking is a documented risk factor. However, the mechanisms of smoking-associated pancreatic carcinogenesis are poorly understood. We have shown that binding of nicotine to nicotinic acetylcholine receptors (nAChRs) expressing subunits α7, α3 and α5 in PDAC and pancreatic duct epithelial cells in vitro triggered the production of the neurotransmitters noradrenaline and adrenaline by these cells. In turn, this autocrine catecholamine loop significantly stimulated cell proliferation via cyclic adenosine 3',5'-monophosphate-dependent signaling downstream of beta-adrenergic receptors. However, the observed responses only represent acute cellular reactions to single doses of nicotine whereas nicotine exposure in smokers is chronic. Using the PDAC cell lines BxPC-3 and Panc-1 and immortalized pancreatic duct epithelial cell line HPDE6-C7, our current experiments reveal a significant sensitization of the nAChR-driven autocrine catecholamine regulatory loop in cells pre-exposed to nicotine for 7 days. The resulting increase in catecholamine production was associated with significant inductions in the phosphorylation of signaling proteins ERK, CREB, Src and AKT, upregulated protein expression of nAChR subunits α3, α4, α5 and α7 and increased responsiveness to nicotine in 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide and cell migration assays. All three cell lines produced the inhibitory neurotransmitter γ-aminobutyric acid, an activity inhibited by gene knockdown of the α4β2nAChR and suppressed by chronic nicotine via receptor desensitization. All of the observed adverse effects of chronic nicotine were reversed by treatment of the cells with γ-aminobutyric acid, suggesting the potential usefulness of this agent for the improvement of PDAC intervention strategies in smokers.
Mohammed H Al-Wadei; Hussein A N Al-Wadei; Hildegard M Schuller
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-07-12
Journal Detail:
Title:  Carcinogenesis     Volume:  33     ISSN:  1460-2180     ISO Abbreviation:  Carcinogenesis     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-08-24     Completed Date:  2012-10-31     Revised Date:  2013-09-03    
Medline Journal Info:
Nlm Unique ID:  8008055     Medline TA:  Carcinogenesis     Country:  England    
Other Details:
Languages:  eng     Pagination:  1745-53     Citation Subset:  IM    
Experimental Oncology Laboratory, Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee Knoxville, TN, USA.
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MeSH Terms
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Epithelial Cells / drug effects
Glutamate Decarboxylase / analysis
Neurotransmitter Agents / physiology*
Nicotine / toxicity*
Pancreatic Ducts / drug effects
Pancreatic Neoplasms / chemically induced*
Receptors, Nicotinic / analysis
gamma-Aminobutyric Acid / analysis,  pharmacology
Grant Support
R01 CA042829/CA/NCI NIH HHS; R01 CA130888/CA/NCI NIH HHS; R01CA042829/CA/NCI NIH HHS; R01CA130888/CA/NCI NIH HHS
Reg. No./Substance:
0/Neurotransmitter Agents; 0/Receptors, Nicotinic; 54-11-5/Nicotine; 56-12-2/gamma-Aminobutyric Acid; EC Decarboxylase; EC decarboxylase 1; EC decarboxylase 2

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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