title: cAMP effects in neuroendocrine tumors: The role of Epac and PKA in cell proliferation and adhesion.
abstract: cAMP effects have been initially attributed to protein kinase A (PKA) activation. Subsequently, two exchange proteins directly activated by cAMP (Epac1/2) have been identified as cAMP targets. Aim of this study was to investigate cAMP effects in pancreatic-NET (P-NET) and bronchial carcinoids and in corresponding cell lines (QGP-1 and H727) on cell proliferation and adhesion and to determine PKA and Epac role in mediating these effects. We found that cAMP increased cyclin D1 expression in P-NET and QGP-1 cells, whereas it had opposite effects on bronchial carcinoids and H727 cells and it promoted cell adhesion in QGP-1 and H727 cells. These effects are mimicked by Epac and PKA specific analogs, activating the small GTPase Rap1. In conclusion, we demonstrated that cAMP exerted divergent effects on proliferation and promoted cell adhesion of different neuroendocrine cell types, these effects being mediated by both Epac and PKA and involving the same effector GTPase Rap1.
authors.affiliation: Laboratory of Cellular and Molecular Endocrinology, IRCCS Clinical and Research Institute Humanitas, Rozzano, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Vitali
authors.affiliation: Laboratory of Cellular and Molecular Endocrinology, IRCCS Clinical and Research Institute Humanitas, Rozzano, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Cambiaghi
authors.affiliation: Fondazione IRCCS Ospedale Maggiore Policlinico, Endocrinology and Diabetology Unit, Department of Clinical Sciences and Community Health, University of Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Spada
authors.affiliation: Laboratory of Cellular and Molecular Endocrinology, IRCCS Clinical and Research Institute Humanitas, Rozzano, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Tresoldi
authors.affiliation: Pancreas Surgery Unit, IRCCS Humanitas Clinical Institute, Rozzano, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Zerbi
authors.affiliation: Fondazione IRCCS Ospedale Maggiore Policlinico, Endocrinology and Diabetology Unit, Department of Clinical Sciences and Community Health, University of Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Peverelli
authors.affiliation: Medical Oncology and Hematology Unit, Cancer Center, Humanitas Clinical and Research Center, Milan, Rozzano, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Carnaghi
authors.affiliation: Fondazione IRCCS Ospedale Maggiore Policlinico, Endocrinology and Diabetology Unit, Department of Clinical Sciences and Community Health, University of Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Mantovani
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Milan, Rozzano, Italy; Endocrinology Unit, Humanitas Research Hospital, Milan, Rozzano, Italy. Electronic address: andrea.lania@humanitas.it.
authors.forename: A G
authors.initials: AG
authors.lastname: Lania
mesh_terms: D002448:Cell Adhesion; D049109:Cell Proliferation; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D018358:Neuroendocrine Tumors / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C116122:RAPGEF3 protein, human; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: CAMP; CAMP-dependent Protein Kinase A (PKA); Exchange proteins directly activated by cAMP (Epac); Neuroendocrine tumors; Ras-like GTPase Rap1