G protein-coupled receptor signaling in human ductal pancreatic cancer cells: Neurotensin responsiveness and mitogenic stimulation

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Abstract
Neuropeptides and their corresponding G protein–coupled receptors (GPCRs) are increasingly implicated in the autocrine/paracrine stimulation of growth of human cancers. We report that neurotensin induced rapid Ca2+ mobilization from intracellular stores followed by Ca2+ influx in five human ductal pancreatic cancer cell lines: HPAF‐II, Capan‐1, Capan‐2, PANC‐1, and MIA PaCa‐2. In addition, most cell lines exhibited Ca2+ responses to multiple neuropeptides including bombesin, bradykinin, cholecystokinin, and vasopressin and to bioactive lipids, including lysophosphatidic acid (LPA), that also act via GPCRs. The well‐differentiated line HPAF‐II responded to at least seven independent GPCR agonists. The concentrations of neurotensin required to induce half‐maximal effects (EC50) in HPAF‐II and PANC‐1 cells were 5 and 8 nM, respectively. Digital fluorescence image analysis to measure Ca2+ responses in single cells revealed that 90% or more of HPAF‐II and PANC‐1 cells responded to 10 nM neurotensin. Addition of neurotensin to PANC‐1 cells also induced rapid and dose‐dependent extracellular‐regulated protein kinase (ERK‐1 and ERK‐2) activation and subsequently, stimulated DNA synthesis. The signaling complexity of GPCRs uncovered by these studies reveals a new aspect in the biology of human pancreatic cancer and could offer the basis for new approaches to the treatment of this disease. J. Cell. Physiol. 186:53–64, 2001.