Recent studies show that gastrointestinal hormones/growth factors may cause cell growth by stimulating multiple intracellular tyrosine phosphorylation (TyrP) signaling cascades as well as by transactivating growth factor receptors. However at present little is known about the ability of many gastrointestinal hormones/growth factors to activate these cascades. In a study on lung cancer cells we investigated the ability of the G-protein coupled receptors for PACAP/VIP to stimulate their growth. We found that the mechanism involved transactivation of the EGF receptor as well as stimulating activation of focal adhesion kinase, paxillin and PYK2, in addition to activation of reactive oxygen species, matrix metalloproteinases and Src. Similar studies are now underway investigating the ability of the GI-neural peptide neurotensin, to stimulate growth of these cells in an autocrine manner as well as the orphan receptor BRS-3, a member of the bombesin receptor family (BN-R). Bombesin-related peptides are particularly important autocrine growth factors for these cancers, and many others, however, many tumor cells posses multiple BN-R receptor subtypes, and the role of the BRS-3 receptor has not be studied until now. With the availability highly selective BRS-3 agonists/antagonists (discussed in pharmacology section) we are now able to perform these studies. Insights from these studies many lead to novel treatments for these cancers. In collaboration with Dr N.Gonzalez(Madrid, Spain) we explored the cellular mechanisms by which the BnR receptor, BRS-3 regulates fat and insulin metabolism. BRS-3 signaling was investigated in dispersed myocytes form normal, obese, or diabetic subjects. Marked differences were found in these different myocytes in the ability of BRS-3 agonists to stimulate GLUT-4 levels, glucose transport, and activate the PI3K signaling cascades, demonstrating alterations in BRS-3 signaling are important in the changes seen in diabetes and obesity. Pancreatic stellate cells are important in both pancreatitis and pancreatic cancer and they are activated by a number of cytokines and G-protein coupled receptors however little is known of their signaling or importance in causing pancreatitis. Three studies in collaboration with Prof Ito, Fukuoka, Japan were performed investigating their signaling in pancreatitis. In one study almost completed, receptors for the GLP1 were found on stellate cells. This could be particularly important because these agents are widely used to treat diabetes and one of their unwanted side-effect is pancreatitis, the mechanism of which is unknown. We found GLP1R receptor increase in number during pancreatitis, in the stellate cells, they activate the MAPK cascade and can cause growth of these cells suggesting they may be involve in this side-effect of GLP1-R usage In another study, the role of the cytokine fractalkine (CXCL1) in pancreatitis was investigate and it was found to be secreted by stellate cells though a MPK mechanism involving metalloproteinase, and this could contribute to the role of stellate cells signaling in causing pancreatitis. In a final study cytosolic double-stranded DNA was shown to show a damage-associated molecular pattern that induced the inflammatory response in pancreatic stellate cells and to be a plausible mechanism for tissue injury-associated pancreatitis. .

Project Start
Project End
Budget Start
Budget End
Support Year
25
Fiscal Year
2013
Total Cost
$712,545
Indirect Cost
City
State
Country
Zip Code
Nuche-Berenguer, Bernardo; Ramos-Álvarez, Irene; Jensen, R T (2016) The p21-activated kinase, PAK2, is important in the activation of numerous pancreatic acinar cell signaling cascades and in the onset of early pancreatitis events. Biochim Biophys Acta 1862:1122-36
Moreno, Paola; Ramos-Álvarez, Irene; Moody, Terry W et al. (2016) Bombesin related peptides/receptors and their promising therapeutic roles in cancer imaging, targeting and treatment. Expert Opin Ther Targets 20:1055-73
Moody, Terry W; Nuche-Berenguer, Bernardo; Jensen, Robert T (2016) Vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide, and their receptors and cancer. Curr Opin Endocrinol Diabetes Obes 23:38-47
Nuche-Berenguer, Bernardo; Ramos-Álvarez, Irene; Jensen, R T (2016) Src kinases play a novel dual role in acute pancreatitis affecting severity but no role in stimulated enzyme secretion. Am J Physiol Gastrointest Liver Physiol 310:G1015-27
Ito, Tetsuhide; Jensen, Robert T (2016) Imaging in multiple endocrine neoplasia type 1: recent studies show enhanced sensitivities but increased controversies. Int J Endocr Oncol 3:53-66
Ito, Tetsuhide; Lee, Lingaku; Jensen, Robert T (2016) Treatment of symptomatic neuroendocrine tumor syndromes: recent advances and controversies. Expert Opin Pharmacother :1-15
Ramos-Álvarez, Irene; Moreno, Paola; Mantey, Samuel A et al. (2015) Insights into bombesin receptors and ligands: Highlighting recent advances. Peptides 72:128-44
González, Nieves; Moreno, Paola; Jensen, Robert T (2015) Bombesin receptor subtype 3 as a potential target for obesity and diabetes. Expert Opin Ther Targets 19:1153-70
Nuche-Berenguer, Bernardo; Moreno, Paola; Jensen, R T (2015) Elucidation of the roles of the Src kinases in pancreatic acinar cell signaling. J Cell Biochem 116:22-36
Moody, Terry W; Moreno, Paola; Jensen, Robert T (2015) Neuropeptides as lung cancer growth factors. Peptides :

Showing the most recent 10 out of 32 publications