Doctoral Dissertations

Date of Award

8-2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Hildegard M. Schuller

Committee Members

Karla Matteson, Michael Fry, and Melissa Kennedy

Abstract

Pancreatic cancer is the fourth leading cause of cancer mortality with a five-year survival rate of less than 5 %. It shows no symptoms until it has reached an advanced stage upon which it has metastasized to distant organs limiting therapeutic options. Several studies have identified smoking, alcohol, diabetes and pancreatitis as risk factors for pancreatic cancer. While smoking is a well-documented risk factor for this malignancy, there still remains a controversy on whether alcohol can act as a risk factor itself or cooperatively enhances the effects of other risk factors.

Previous reports provide evidence that nicotinic acetylcholine receptors (nAChRs) and beta-adrenergic receptors cooperatively stimulate the growth and migration of normal and pancreatic ductal adenocarcinoma (PDAC) cells upon binding NNK. Binding of the nicotine-derived nitrosamine ketone (NNK) to nAChRs result in neurotransmitters production regulation. These neurotransmitters in turn act as agonists to β-ARs [beta-adrenergic receptors] thereby activating adenylyl cyclase and the subsequent cAMP dependent signaling pathways. This ultimately results in the stimulation of proliferation, migration and angiogenesis and inhibition of apoptosis.

Using assays for the assessment of adrenaline, noradrenaline, GABA and cAMP production; PKA activity; CREB, Src, Akt and ERK phosphorylation; and cell proliferation and migration, we have identified an autocrine catecholamine loop that is jointly regulated by α3, 5 and 7-nAChRs [alpha 3, 5 and 7-nicotinic acetylcholine receptors] in normal pancreatic ductal epithelial cells (HPDE6-C7) and PDAC cell lines (BxPC-3 and Panc-1) upon stimulation by nicotine or ethanol. This catecholamine loop in turn acts to stimulate growth of normal and PDAC cell lines via cAMP dependent signaling pathways downstream β-ARs [beta-adrenergic receptors]. This loop however, is interrupted upon γ-amino butyric acid [gamma-amino butyric acid] (GABA) treatment of cells at the level of adenylyl cyclase activation thereby inhibiting nicotine and ethanol-induced stimulatory effects on cell proliferating and migration.

Our study findings therefore suggest smoking and chronic alcohol intake to be risk factors for the development of PDAC. These agents regulate catecholamine and GABA synthesis via modulation of nAChRs thereby stimulating proliferation and migration and inhibiting apoptosis. The observed effects of nicotine and ethanol were all reversed by treatment of cells with GABA, suggesting it as a potential therapeutic agent for the treatment and prevention of this malignancy.

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