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Pancreas. 2006 Jul;33(1):53-62.

Ethanol and the tobacco-specific carcinogen, NNK, contribute to signaling in immortalized human pancreatic duct epithelial cells.

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  • 1Experimental Oncology Laboratory, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA.

Abstract

OBJECTIVES:

Smoking is a well-documented risk factor for pancreatic cancer. The tobacco-specific nitrosamine, NNK (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanone), significantly induces pancreatic ductal adenocarcinomas in laboratory rodents. Recent observations suggest that ethanol enhances the tumorigenic effects of smoking. Ethanol consumption is associated with the development of chronic pancreatitis, also considered a predisposing factor for pancreatic ductal adenocarcinoma. Because the precise role of ethanol in pancreatic carcinogenesis is not known, this study sought to elucidate the cumulative effects of ethanol and NNK on particular signal transduction pathways that might play a role in cell proliferation in immortalized human pancreatic duct epithelial cells.

METHODS:

The HPDE6-c7 cells are developed from pancreatic duct epithelial cells, which are the putative cells of origin of pancreatic ductal adenocarcinoma. Cell proliferation assays, Western blot, and cyclic adenosine monophosphate assays were used to demonstrate the effects of ethanol and NNK treatments on these cells.

RESULTS:

Ethanol cotreatments enhanced the NNK-induced proliferation of these cells. This response was inhibited by the adenylyl cyclase, protein kinase A, mitogen-activated protein kinase (p42/p44), and epidermal growth factor receptor-specific tyrosine kinase inhibitors. Cotreatments of NNK and ethanol also increased cyclic adenosine monophosphate accumulation, cAMP response element-binding family of proteins and mitogen-activated protein kinase phosphorylation, and protein kinase A activation.

CONCLUSIONS:

These findings suggest a potential role for these pathways contributing to the development of smoking- and alcohol-related pancreatic carcinogenesis.

PMID:
16804413
[PubMed - indexed for MEDLINE]
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