Objective: The effect of neurotensin (NT) on in vitro growth of human pancreatic cancer cells (MIA PaCa-2) was examined. Furthermore, the intracellular signal-transduction pathways by which neurotensin regulates growth of MIA PaCa-2 cells were determined. Summary Background Data: NT is trophic for normal rat pancreas, but the effect of NT on growth of human pancreatic cancer is not known. Methods: Effects of NT (10-12 to 10-6 mol/l) on growth of MIA PaCa-2 cells were determined by both count of cell numbers and 3H-thymidine incorporation. Action of NT on phosphatidylinositol (Pl) hydrolysis, cyclic AMP production, and intracellular calcium level were determined by conventional methods. The effects of 8-bromo-cyclic AMP and prostaglandin E2 on cell growth were determined. Results: Low concentrations of NT (10-12 to 10-9 mol/l) stimulated growth in a dose-dependent manner, but higher concentrations of NT (10-8 to 10-6 mol/l) did not stimulate growth of MIA PaCa-2 cells. NT (10-12 to 10-6 mol/l) stimulated Pl hydrolysis and increased intracellular calcium levels in a dose-dependent manner. High concentrations of NT (10-8 to 10-6 mol/l) stimulated production of cyclic AMP in a dose-dependent manner. 8-bromo-cyclic AMP inhibited growth of MIA PaCa-2 cells; prostaglandin E2 did not affect growth of MIA PaCa-2 cells. Conclusions: NT stimulates growth of MIA PaCa-2 cells through stimulation of Pl hydrolysis and mobilization of calcium. Stimulation of the cyclic AMP pathway by high concentrations of NT abolishes the growth-stimulatory effect of NT that is mediated through Pl hydrolysis or calcium mobilization.
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