Pancreatic cancer is the 4th leading cause of cancer fatalities in the United States both in men and women, with an overall 5-year survival rate of only 3-5%. As the current therapies offer very limited survival benefits, novel therapeutic strategies are urgently needed to treat this aggressive disease. Given the close relationship between the endocrine and exocrine pancreas, a unique feature of the pancreatic microenvironment is the potential influence of locally produced insulin on pancreatic cancer cell development. Crosstalk between the insulin receptor and G protein-coupled receptor (GPCR) signaling systems plays a critical role in the regulation of many physiological functions and in the pathogenesis of a variety of abnormal processes, including cancer cell proliferation. Despite the biological and clinical importance of this receptor crosstalk, the molecular mechanism(s) involved remain poorly characterized. This R21 application (in response to RFA, entitled """"""""Pilot Studies in Pancreatic Cancer"""""""") is based on our recent findings showing that exposure of human pancreatic cancer cells to physiological concentrations of insulin rapidly enhances early cellular events, such as increase in [Ca2+]i elicited by Gq-coupled receptor agonists, including angiotensin II, bradykinin, bombesin and neurotensin. Using real-time imaging of changes in PtdIns(4,5)P2 hydrolysis and generation of Ins(1,4,5)P3 in single cells, we found that insulin enhances the rate and magnitude of these second messenger-generating responses. The insulin-induced potentiation of GPCR signaling is mediated through a rapamycin-sensitive, PI3- kinase/mTOR-dependent pathway. Our preliminary results also show that insulin and GPCR agonists synergistically stimulate DNA synthesis and anchorage-independent cell proliferation. We hypothesize that the potentiation of GPCR signaling by insulin through a mTOR-dependent pathway provides a mechanism by which insulin enhances the responsiveness of pancreatic cells to GPCR agonists, Metformin, a widely used drug for treatment of type 2 diabetes mellitus, negatively regulates mTOR function via AMPK activation. We hypothesize that metformin preferentially abolishes the crosstalk between insulin receptor and GPCR signaling. Indeed, preliminary results show that metformin inhibits the crosstalk between insulin receptor and GPCR signaling systems in Ca2+ signaling and DNA synthesis in human pancreatic cancer cells. Consequently, we propose to pursue two Specific Aims in this Grant application: 1) Characterize the mechanism(s) and growth-promoting effects of the crosstalk between insulin receptor and GPCR signaling in a panel of human pancreatic cancer cell lines;2) Characterize the inhibitory effects of metformin on the crosstalk between insulin receptor and GPCR signaling in vitro and in vivo. Given that metformin and rapamycin derivatives are FDA-approved drugs, these studies may pave the way for exciting and rapid translational research.
Conditions that enhance insulin production in the pancreas, including obesity and early stages of Type II diabetes, increase the risk of pancreatic cancer. An exciting new result shown in this application is that metformin, a drug widely used in the treatment of type II diabetes, inhibits a novel crosstalk between insulin receptor and Gq-coupled receptor signaling, blocks the growth of human pancreatic cancer cells and thus, can provide a novel therapeutic strategy for pancreatic cancer.
|Sinnett-Smith, James; Kisfalvi, Krisztina; Kui, Robert et al. (2013) Metformin inhibition of mTORC1 activation, DNA synthesis and proliferation in pancreatic cancer cells: dependence on glucose concentration and role of AMPK. Biochem Biophys Res Commun 430:352-7|
|Kisfalvi, Krisztina; Moro, Aune; Sinnett-Smith, James et al. (2013) Metformin inhibits the growth of human pancreatic cancer xenografts. Pancreas 42:781-5|
|Yoo, James; Rodriguez Perez, Citlali Ekaterina; Nie, Wenxian et al. (2012) TNF-ýý induces upregulation of EGFR expression and signaling in human colonic myofibroblasts. Am J Physiol Gastrointest Liver Physiol 302:G805-14|
|Waldron, Richard T; Innamorati, Giulio; Torres-Marquez, M Eugenia et al. (2012) Differential PKC-dependent and -independent PKD activation by G protein ? subunits of the Gq family: selective stimulation of PKD Ser??? autophosphorylation by G?q. Cell Signal 24:914-21|
|Rodriguez Perez, Citlali Ekaterina; Nie, Wenxian; Sinnett-Smith, James et al. (2011) TNF-? potentiates lysophosphatidic acid-induced COX-2 expression via PKD in human colonic myofibroblasts. Am J Physiol Gastrointest Liver Physiol 300:G637-46|
|Yoo, James; Rodriguez Perez, Citlali Ekaterina; Nie, Wenxian et al. (2011) Protein kinase D1 mediates synergistic MMP-3 expression induced by TNF-? and bradykinin in human colonic myofibroblasts. Biochem Biophys Res Commun 413:30-5|
|Ochi, Nobuo; Tanasanvimon, Suebpong; Matsuo, Yoichi et al. (2011) Protein kinase D1 promotes anchorage-independent growth, invasion, and angiogenesis by human pancreatic cancer cells. J Cell Physiol 226:1074-81|
|Rozengurt, Enrique (2011) Protein kinase D signaling: multiple biological functions in health and disease. Physiology (Bethesda) 26:23-33|
|Young, Steven H; Rozengurt, Enrique (2010) Crosstalk between insulin receptor and G protein-coupled receptor signaling systems leads to Ca²+ oscillations in pancreatic cancer PANC-1 cells. Biochem Biophys Res Commun 401:154-8|
|Rozengurt, Enrique; Sinnett-Smith, James; Kisfalvi, Krisztina (2010) Crosstalk between insulin/insulin-like growth factor-1 receptors and G protein-coupled receptor signaling systems: a novel target for the antidiabetic drug metformin in pancreatic cancer. Clin Cancer Res 16:2505-11|
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