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Pancreatic duct cells are equipped with acid/base transporters important for exocrine secretion. Pancreatic ductal adenocarcinoma (PDAC) cells may utilize such transporters to acidify extracellular tumor microenvironment, creating a niche favoring cell proliferation, fibrosis and resistance to chemotherapy—all contributing to the notoriously bad prognosis of this disease. Here, we report that gastric and non-gastric H+, K+-ATPases (coded by ATP4A and ATP12A) are overexpressed in human and murine pancreatic cancer and that we can target them specifically with proton pump inhibitors (PPIs) and potassium-competitive acid blockers (P-CABs) in in vitro models of PDAC. Focusing on pantoprazole, we show that it significantly reduced human cancer cell proliferation by inhibiting cellular H+ extrusion, increasing K+ conductance and promoting cyclin D1-dependent cell cycle arrest and preventing STAT3 activation. Pantoprazole also decreased collagen secretion from pancreatic stellate cells. Importantly, in vivo studies show that pantoprazole treatment of tumor-bearing mice reduced tumor size, fibrosis and expression of angiogenic markers. This work provides the first evidence that H+, K+-ATPases contribute to PDAC progression and that these can be targeted by inhibitors of these pumps, thus proving a promising therapeutic strategy.

Introduction: Peripheral correlates of age-associated cognitive decline are important tools in the screening for potentially abnormal courses of cognitive aging. Since salivary gland function is controlled by the autonomic and central nervous system, associations between cognitive changes and salivary gland hypofunction were tested in two groups of middle-aged men in late midlife, who differed substantially with respect to their midlife performance in verbal intelligence when compared with their performance in young adulthood. Materials and Methods: Participants (n = 193) were recruited from the Danish Metropolit Cohort of men born in 1953. Based on their individual change in performance in two previously administered intelligence tests, they were allocated to one group of positive and one group of negative outliers in midlife cognition scores, indicating no decline versus decline in test performance. All participants underwent a clinical oral examination including assessments of their dental, periodontal, and mucosal conditions. Whole and parotid saliva flow rates were measured, and the number of systemic diseases and medication intake as well as daytime and nocturnal xerostomia were registered. Results: Participants with decline in cognitive test performance in midlife had significantly lower unstimulated whole saliva flow rates, higher prevalence of hyposalivation and daytime xerostomia and a higher caries experience than participants with no decline in midlife performance. Daytime and nocturnal xerostomia were associated with daily intake of medication and alcohol. Discussion: Overall, hyposalivation, xerostomia and poor dental status distinguished a group of men displaying relative decline in cognitive performance from a group of men without evidence of cognitive decline. Thus, hyposalivation and poor dental health status may represent potential correlates of age-related cognitive decline in late midlife, provided that other causes ca

Udgivelsesdato: May 2003, ATP and other nucleotides are released from various cells, but the pathway and physiological stimulus for ATP release are often unclear. The focus of our studies is the understanding of ATP release and signaling in rat exocrine pancreas. In acinar suspension mechanical stimulation, hypotonic shock and, most importantly, cholinergic stimulation released 5-20nM ATP into the medium, as monitored by luminescence of the luciferin/luciferase reaction. ATP release was visualized at the single acinus level as luciferin consumption detected by confocal laser scanning microscopy (CLSM). The estimated ATP concentrations were higher, about 10µM, around acinar cells after cholinergic stimulation. Fluorescence of quinacrine and MANT-ATP indicated that some ATP is stored in secretory granules. Pancreatic acini have transcripts for P2X1, P2X4, P2Y2, and P2Y4 receptors, but measurements of Ca2+ signals in isolated acini using Fura-2 and CLSM revealed that only about 15% of acini respond to extracellular ATP or UTP. Hence, in acini only a few P2 receptors are functional and the distribution seems heterogenous. In contrast, pancreatic ducts have transcripts for P2Y2, P2Y4, P2X4, and P2X7 receptors that consistently increase intracellular Ca2+. Patch-clamp studies show that P2Y2/P2Y4 receptors inhibit K+ channels, and thus downregulate secretion. P2X4/P2X7 channels stimulate Na+/Ca2+ influx and may upregulate secretion by yet unknown mechanisms. Taken together, our studies show that pancreatic acini release ATP, primarily in response to cholinergic stimulation, and thus ATP may be a paracrine mediator between pancreatic acini and ducts. Drug Dev. Res. 59:128-135, 2003. © 2003 Wiley-Liss, Inc.

ATP, confocal microscope, pancreas, P2 receptors