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 neurotensin to stimulate their growth. We found that the mechanism involved transactivation of the EGF receptor as well as stimulating activation of reactive oxygen species, matrix metalloproteinases and Src. SI RNA for NT receptors 1 reduced the ability the NTS1 anatagonist,SR48692, to inhibit the growth of the lung cancer cells. THe antagonist potentiated the inhibitory action of gefitinib. Similar studies were performed with neuroendocrine tumor cells and the growth effects of various GI hormones (bombesin, Neurotenisn, PACAP) were mediated in a similar manner. These results suggest inhibition of the EGFR signaling cascade by GI hormones may be a useful therapeutic approach. 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. BRS3 agonists increased activity of MAPK,p90RSK1, PKB, PI3K,and P70sgK. It also stimualted glycogen synthetase a activity and glycogen synthesis.. Myocytes from obesity or diabetic patients were mor sensitive. 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. Two studies in collaboration with Prof Ito, Fukuoka, Japan were performed investigating their signaling in pancreatitis. In one 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 second study 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 a final study the role of Src kinase activation by the GI hormone CCk was studied in detail in pancreatic acinar cells using three different approaches.: a specific SFK inhibitor with inactive control, over expression by adenovirus of SFK stimulants or inhibitors. These resulted demonstrated that SFK were involved in a number of cellular processes important in growth, secretion, movement and in the response of these cells to pathological processes such as pancreatitis.
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