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

Abstract

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 Ca(2+) 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.

Pituitary Adenylate Cyclase-Activating Polypeptide Causes Increased Tyrosine Phosphorylation of Focal Adhesion Kinase and Paxillin

“…PACAP-27 addition to lung cancer cells causes increased cAMP, ERK phosphorylation, c-fos mRNA and VEGF expression (Draoui et al 1996;Moody et al 2002a). PACAP stimulates the growth of lung cancer (NCI-H345 cells; Moody et al 1993a), pancreatic carcinoma (AR42-J cells; Buscail et al 1992), and colon cancer cells (Bon cells; Germano et al 2009). PACAP(6-38) is a PAC1-R antagonist which inhibits the proliferation of lung, breast and prostate cancer cells (Zia et al 1995;Leyton et al 1999).…”

Pituitary Adenylate Cyclase-Activating Polypeptide Causes Tyrosine Phosphorylation of the Epidermal Growth Factor Receptor in Lung Cancer Cells

“…The addition of PACAP to NCI-H838 cells causes ERK phosphorylation, increases c-fos mRNA, and in-creases vascular endothelial growth factor expression (Draoui et al, 1996;Moody et al, 2002). PACAP stimulates the growth of lung cancer (NCI-H345 cells; Moody et al, 1993), pancreatic carcinoma (AR42-J cells; Buscail et al, 1992), and colon cancer (Bon cells; Germano et al, 2009). PACAP(6 -38) is a PAC1 antagonist that inhibits the proliferation of lung, breast, and prostate cancer cells (Zia et al, 1995;Pisegna et al, 1997;Leyton et al, 1998).…”

Examination of PACAP-Like Immunoreactivity in Urogenital Tumor Samples

“…PACAP inhibits growth of myeloma cells (Arimura et al 2006a, b), of serum-starved glioma cells (D'Amico et al 2013), and of cervical carcinoma (Lee et al 2014), as well as proliferation in primary medulloblastomaderived tumorsphere cultures (Cohen et al 2010). On the other hand, PACAP stimulates the growth of colon (Le et al 2002), small cell lung cancer (Moody et al 1993), astrocytoma , glioblastoma cells (Dufes et al 2003;Sokolowska and Nowak 2008) as well as pancreatic carcinoma cells (Schafer et al 1996;Germano et al 2009). PACAP(6-38), the antagonist of PAC1 receptor, inhibits the growth of prostate cancer (Leyton et al 1998), breast cancer (Leyton et al 1999), and non-small cell lung cancer cells (Zia et al 1995).…”