Cigarette smoking is a recognized risk factor for the induction of pancreatic diseases and is suspected to play a major role in the development of pancreatic cancer in smokers.
This study was designed to characterize the mechanisms of nicotine-induced injury to the pancreas. AR42Jcells, a stable mutant pancreatic tumor cell line, was chosen for the study because of its stability in culture media and also because of its known secretory capacity, which is like that of a normal pancreatic acinar cell. It is hypothesized that nicotine-induced effects on the pancreas are triggered by oxidative stress induced in pancreatic acinar cell via oxidative stress signaling pathways.
The results from our study showed that, in vitro, nicotine induced generation of oxygen free radicals measured as malondialdehyde, an end product of lipid peroxidation. Treatment of AR42J cells with nicotine induced p-ERK 1/2 activation as confirmed by Western blot and immunofluorescence imaging of cytoplasmic localization of mitogen-activated protein kinase (MAPK) signals. Nicotine enhanced AR42J cell proliferation and cholecystokinin-stimulated amylase release in AR42J cells. These effects of nicotine were confirmed by simultaneous studies conducted on the same cells by hydrogen peroxide, a known oxidative biomarker. Allopurinol, a XOD inhibitor, suppressed these effects induced by nicotine and H(2)O(2) with the exception that cholecystokinin-stimulated amylase release by H(2)O(2) remained unaltered when AR42J cells were preincubated with allopurinol. These results suggest that nicotine-induced effects on pancreatic acinar cells were associated with generation of oxyradical mediated via the XOD pathway. The results have a direct impact on cell proliferation, MAPK signaling, and acinar cell function.
We conclude that nicotine induces oxidative stress in pancreatic acinar cells and that these events trigger pathophysiological changes in the pancreas, leading to increased cell proliferation and injury.
"Such changes have been linked to morphological changes observed during pancreatitis  . Nicotine has also been shown to modulate oxidative stress and lipid peroxidation although it is unclear if these processes participate in the pathophysiology of acute and chronic pancreatitis . "
[Show abstract][Hide abstract] ABSTRACT: Smoking is a major risk factor for chronic pancreatitis and pancreatic cancer. However, the mechanisms through which it causes the diseases remain unknown. In the present manuscript we reviewed the latest knowledge gained on the effect of cigarette smoke and smoking compounds on cell signaling pathways mediating both diseases. We also reviewed the effect of smoking on the pancreatic cell microenvironment including inflammatory cells and stellate cells.
Journal of Cancer Therapy 11/2013; 4(10A):34-40. DOI:10.4236/jct.2013.410A005
"In earlier studies the effect of nicotine on cell signaling and function in this cell system and in rat tumorigenic cell line has been reported from this laboratory
[28-30]. However, the precise mechanism by which nicotine induces the enhancement of the acinar cell function was not shown. "
[Show abstract][Hide abstract] ABSTRACT: Background
Nicotine is a risk factor for pancreatitis resulting in loss of pancreatic enzyme secretion. The aim of this study was to evaluate the mechanisms of nicotine-induced secretory response measured in primary pancreatic acinar cells isolated from Male Sprague Dawley rats. The study examines the role of calcium signaling in the mechanism of the enhanced secretory response observed with nicotine exposure.
Isolated and purified pancreatic acinar cells were subjected to a nicotine exposure at a dose of 100 μM for 6 minutes and then stimulated with cholecystokinin (CCK) for 30 min. The cell’s secretory response was measured by the percent of amylase released from the cells in the incubation medium Calcium receptor antagonists, inositol trisphosphate (IP3) receptor blockers, mitogen activated protein kinase inhibitors and specific nicotinic receptor antagonists were used to confirm the involvement of calcium in this process.
Nicotine exposure induced enhanced secretory response in primary cells. These responses remained unaffected by mitogen activated protein kinases (MAPK’s) inhibitors. The effects, however, have been completely abolished by nicotinic receptor antagonist, calcium channel receptor antagonists and inositol trisphosphate (IP3) receptor blockers.
The data suggest that calcium activated events regulating the exocytotic secretion are affected by nicotine as shown by enhanced functional response which is inhibited by specific antagonists… The results implicate the role of nicotine in the mobilization of both intra- and extracellular calcium in the regulation of stimulus-secretory response of enzyme secretion in this cell system. We conclude that nicotine plays an important role in promoting enhanced calcium levels inside the acinar cell.
[Show abstract][Hide abstract] ABSTRACT: It is evident that various types of tumor cells use different mechanisms to inhibit apoptosis. Recent increased understanding
of the many factors involved in the apoptotic process has identified potential targets for the restoration of the apoptotic
response in pancreatic tumor cells. The ultimate goal is to develop effective therapeutic strategies to control this devastating
disease. The aim of this chapter is to review signaling pathways involved in apoptosis by providing an account of the signaling
molecules involved. This chapter reviews the literature on traditional apoptotic signaling pathways with special emphasis
on pancreatic cancer. Involvement of G-protein coupled receptors and inositol phosphates in pancreatic apoptosis is also reviewed.
Finally we have reviewed the literature on nutritional impacts on pancreatic apoptosis as an example of an environmental risk
factor for pancreatic cancer. Knowledge about diverse effects on signaling molecules may serve as a basis for pancreatic cancer
chemotherapeutic applications focused on apoptotic mechanisms.
L Pellegrini, G Belcaro, M Dugall, S Hu, G Gizzi, M Corsi, M Hosoi, R Luzzi, B Feragalli, R Cotellese
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