Journal of Molecular Neuroscience

, Volume 39, Issue 3, pp 391–401 | Cite as

PACAP Induces Signaling and Stimulation of 5-Hydroxytryptamine Release and Growth in Neuroendocrine Tumor Cells

  • Patrizia M. GermanoEmail author
  • Sandy N. Lieu
  • Janjing Xue
  • Helen J. Cooke
  • Fievos L. Christofi
  • Yuxin Lu
  • Joseph R. Pisegna


Neuroendocrine tumors, although rare, are currently diagnosed with increasing frequency, owing to improved imaging techniques and a greater clinical awareness of this condition. To date, BON is a very well established and characterized human pancreatic neuroendocrine tumor cell line used to study the signal transduction and genetic regulation of neuroendocrine tumors secretion and growth. The secretory activity of BON cells is known to release peptides, such as chromogranin A, neurotensin, and biogenic amines, as 5-HT, permitting an assessment of their biological activity. The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP), released from the enteric neurons in the gastrointestinal tract by binding to its high affinity receptor PAC1, has been previously shown to regulate the secretory activity and growth of the neuroendocrine-derived enterochromaffin-like cells in the stomach. This led us to speculate that PACAP might also play an important role in regulating the growth of human neuroendocrine tumors. Accordingly, in the current study, we have shown that BON cells express PAC1 receptors, which are rapidly internalized upon PACAP activation. Furthermore, PAC1 receptor activation, in BON cells, couple to intracellular Ca2+ as well as cAMP responses and induce the release of intracellular 5-HT, activate mitogen activated protein kinases, and stimulate cellular growth. These data indicate that PACAP functionally can stimulate 5-HT release and promote the growth of the BON neuroendocrine tumor cell line. Therefore, PACAP and its receptors regulate neuroendocrine tumor secretory activity and growth in vivo, and this knowledge will permit the development of novel diagnostic and therapeutic targets for managing neuroendocrine tumors in humans.


BON cell Carcinoid tumor PACAP 



This work was supported by the Department of Veterans Affairs Merit Review Grant (JRP) and National Institutes of Health DK37240 (HJC).


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Copyright information

© Humana Press 2009

Authors and Affiliations

  • Patrizia M. Germano
    • 1
    Email author
  • Sandy N. Lieu
    • 1
  • Janjing Xue
    • 2
  • Helen J. Cooke
    • 2
  • Fievos L. Christofi
    • 2
  • Yuxin Lu
    • 1
  • Joseph R. Pisegna
    • 1
  1. 1.CURE: Digestive Diseases Research Center, VA Greater Los Angeles Healthcare System and Department of MedicineUniversity of CaliforniaLos AngelesUSA
  2. 2.Departments of Neuroscience and AnesthesiologyThe Ohio State UniversityColumbusUSA

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