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

J Cell Physiol. 2001 Jan;186(1):53-64. doi: 10.1002/1097-4652(200101)186:1<53::AID-JCP1004>3.0.CO;2-Q.


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 8nM, 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 10nM 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bombesin / pharmacology
  • Calcium / physiology
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • GTP-Binding Proteins / metabolism*
  • Humans
  • Image Processing, Computer-Assisted
  • Intracellular Membranes / metabolism
  • Microscopy, Fluorescence
  • Mitogen-Activated Protein Kinases / metabolism
  • Mitogens / pharmacology
  • Neurotensin / pharmacology
  • Osmolar Concentration
  • Pancreatic Ducts*
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / physiopathology*
  • Receptors, Cell Surface / agonists
  • Receptors, Cell Surface / antagonists & inhibitors
  • Receptors, Cell Surface / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Tumor Cells, Cultured


  • Mitogens
  • Receptors, Cell Surface
  • Neurotensin
  • Mitogen-Activated Protein Kinases
  • GTP-Binding Proteins
  • Bombesin
  • Calcium