Ethanol and the tobacco-specific carcinogen, NNK, contribute to signaling in immortalized human pancreatic duct epithelial cells.
OBJECTIVE
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.
Askari
Minoo D F
MD
Experimental Oncology Laboratory, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA.
Tsao
Ming-Sound
MS
Cekanova
Maria
M
Schuller
Hildegard M
HM
D050882:CREB-Binding Protein / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism; D003043:Cocarcinogenesis; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009602:Nitrosamines / Q000633:toxicity*; D010183:Pancreatic Ducts / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction
D002273:Carcinogens; D009602:Nitrosamines; D000431:Ethanol; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D000242:Cyclic AMP; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3