Interaction of beta-adrenergic receptors, NNK, and ethanol in selected pancreatic carcinoma cell lines

Author

Diann Lynn Weddle

Date of Award

12-1999

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Hildegard Schuller

Committee Members

David O. Slauson, Kevin Hahn, John L. Bell

Abstract

Pancreatic carcinoma is the leading cause of cancer death in people although it ranks 11th in overall cancer incidence. The most common primary malignancy of the pancreas is ductal adenocarcinoma which represents 75% of all exocrine pancreatic neoplasms. The pathophysiology of pancreatic carcinoma remains unclear, if not controversial. Tobacco and alcohol are risk factors. Ki-ras and p53 commonly occur in genetic mutations, 75% and 50% respectively. However, the interconnection between these risk factors and genetic mutations and their role in pancreatic carcinogenesis has not been consistent. It has been reported that patients who smoke and drank had a lower incidence ofKi-ras mutations than patients who only smoked or consumed alcohol. Furthermore, it has been reported that patients without p53 or Ki-ras mutations have shorter survival times than patients who had one of the mutations.In a transplacental hamster model, it was shown that the tobacco-specific nitrosamine4-(methylnitrosamine>l-(3-pyritiyl)-l-butanone (NNK) caused exocrine pancreatic adenocarcinoma in the offering of pregnant hamsters pre-exposed to ethanol in the drinking water, where as exposure to NNK alone caused tumors of the respiratory tract. It has been demonstrated that these pancreatic tumors iii the offspring of dams that received ethanol did not have p53 or Ki-ras mutations and appeared to develop tumors independent of these alterations. Tobacco is also a risk factor for various pulmonary cancers. A beta-adrenergic receptor mediated mitogenic pathway has been identified in human peripheral pulmonary adenocarcinoma cell lines. NNK has also been shown to bind to beta-adrenergic receptors in these cells.Using radioligand binding techniques, β₁, and β₂ -adrenergic receptor subtypes were found in membrane preparations from fetal hamster pancreas and from 4 human pancreatic adenocarcinoma cell lines. In the fetal hamster pancreas of offspring from dams who did not receive ethanol, there was a higher proportion of β₁ receptors. In the fetal pancreas of offspring from ethanol treated dams and in the human pancreatic carcinoma cell lines, higher proportion of β₂ receptors was demonstrated. As studied with competition assays in the fetal pancreas, NNK bound to the beta-adrenergic receptors. In the ethanol treated pancreas, the competition curve shifted to the left suggesting an increased affinity of NNK to the receptors. As studied by 3^H-thymidine incorporation, increasing concentrations ofNNK did not result in increased DNA synthesis. Maintenance of these cell lines in media containing ethanol did not change this observation. However, simultaneous treatment withNNK and a β₂-antagonist resulted in marked inhibition of DNA synthesis in all cell lines under both general and ethanol media maintenance conditions.These findings did not fully support the central hypothesis that NNK would induce proliferation of human pancreatic carcinoma cell lines through beta-adrenergic receptors and that the effect would be enhanced in the presence of ethanol. These findings did demonstrate a potential role of beta-adrenergic receptors, particularly , β₂ perhaps in concert with NNK,in the cell cycle regulation of these cells.Chronic alcohol consumption is a risk factor for chronic pancreatitis which is also a risk factor for pancreatic cancer. Beta-adrenergic receptors have been shown to activate. pathways involving phospholipases which can trigger the release of arachidonic acid. Recent Evidence has demonstrated that cyclooxygenase-2 expression is upregulated in human pancreatic adenocarcinomas. These findings together suggest that a link between beta adrenergic receptors and the arachidonic acid pathway may exist and provide a pathophysiologic role in the development of this cancer type.

Recommended Citation

Weddle, Diann Lynn, "Interaction of beta-adrenergic receptors, NNK, and ethanol in selected pancreatic carcinoma cell lines. " PhD diss., University of Tennessee, 1999.
https://trace.tennessee.edu/utk_graddiss/8943