ECE2014 Poster Presentations Endocrine tumours and neoplasia (99 abstracts)
The effects of cAMP in different neuroendocrine tumorous cells: the role of Epac and PKA in cell proliferation and cell adhesion
Eleonora Vitali 1 , Valeria Cambiaghi 1 , Alessandro Zerbi 2 , Erika Peverelli 3 , Giovanna Mantovani 3 , Federica Loiarro 1 , Carlo Carnaghi 4 , Anna Spada 3 & Andrea Lania 1,
1Laboratory of Cellular and Molecular Endocrinology, IRCCS Clinical and Research Institute Humanitas, Rozzano, Italy; 2Pancreas Surgery Unit, IRCCS Humanitas Clinical Institute, Rozzano, Italy; 3Endocrine Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ospedale Maggiore Policlinico, University of Milan, Milan, Italy; 4Medical Oncology and Hematology Unit, Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy; 5Biometra Department, Neurosurgery Department, IRCCS Humanitas Clinical Institute, University of Milan, Rozzano, Italy.
cAMP is an ubiquitous second messenger that is implicated in the regulation of a wide variety of cell functions, including cell proliferation that is differently affected depending on the cell type. Although the effects exerted by cAMP were initially attributed to PKA activation, two exchange proteins directly activated by cAMP (Epac1/2) have been identified as cAMP targets able to mediate several cAMP effects. Aim of this study was to investigate the effect of cAMP on neuroendocrine tumor cells proliferation and to identify PKA and Epac differential involvement.
The activation of cAMP pathway by forskolin induced a significant increase in BrDU incorporation and cyclin D1 expression in both cultured human gastroenteropancreatic-NET cells and QGP1 cell line. Conversely, cAMP increase by forskolin induced cell proliferation inhibition in carcinoid cell line H727 (33±4%, P<0.05 vs basal).
The divergent cAMP effects were mimicked by Epac and PKA analogs which activated Rap1 and CREB respectively. In particular, in QGP1 cells, both Epac- and PKA-selective analogs induced a similar stimulatory effect on cell proliferation (36±6 and 37±5%, respectively; P: NS). Similarly, in H727 cells a comparable inhibitory effects on cell proliferation was observed after both Epac and PKA selective activation (35±10 and 30±3% inhibition, P: NS).
Finally, Epac and PKA activators induced an increase of cell adhesion in QGP1 cells (48±8 and 32±5%,respectively; P<0.05 vs basal), this stimulatory effect being mediated by Epac analog only in H727 cells (63±12%, P<0.05 vs basal).
Our study indicates that cAMP induces positive or negative effects on neuroendocrine cell line proliferation, depending on the cell type, and that both Epac and PKA participate by activating different and partially unidentified signaling pathways. The previously unrecognized role of Epac as a mediator of cAMP effects in neuroendocrine cells open the way for the identification of molecular mechanisms underlying the pathogenesis of neuroendocrine tumors and may represent the basis for new therapeutic targets.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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