title: IGF-1 drives chromogranin A secretion via activation of Arf1 in human neuroendocrine tumour cells.
abstract: Hypersecretion is the major symptom of functional neuroendocrine tumours. The mechanisms that contribute to this excessive secretion of hormones are still elusive. A key event in secretion is the exit of secretory products from the Golgi apparatus. ADP-ribosylation factor (Arf) GTPases are known to control vesicle budding and trafficking, and have a leading function in the regulation of formation of secretory granula at the Golgi. Here, we show that Arf1 is the predominant Arf protein family member expressed in the neuroendocrine pancreatic tumour cell lines BON and QGP-1. In BON cells Arf1 colocalizes with Golgi markers as well as chromogranin A, and shows significant basal activity. The inhibition of Arf1 activity or expression significantly impaired secretion of chromogranin A. Furthermore, we show that the insulin-like growth factor 1 (IGF-1), a major regulator of growth and secretion in BON cells, induces Arf1 activity. We found that activation of Arf1 upon IGF-1 receptor stimulation is mediated by MEK/ERK signalling pathway in BON and QGP-1 cells. Moreover, the activity of Arf1 in BON cells is mediated by autocrinely secreted IGF-1, and concomitantly, autocrine IGF1 secretion is maintained by Arf1 activity. In summary, our data indicate an important regulatory role for Arf1 at the Golgi in hypersecretion in neuroendocrine cancer cells.
authors.affiliation: Department of Internal Medicine I, University of Ulm, Ulm, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Münzberg
authors.forename: Katharina
authors.initials: K
authors.lastname: Höhn
authors.forename: Denis
authors.initials: D
authors.lastname: Krndija
authors.forename: Ulrike
authors.initials: U
authors.lastname: Maaß
authors.forename: Detlef K
authors.initials: DK
authors.lastname: Bartsch
authors.forename: Emily P
authors.initials: EP
authors.lastname: Slater
authors.forename: Franz
authors.initials: F
authors.lastname: Oswald
authors.forename: Paul
authors.initials: P
authors.lastname: Walther
authors.forename: Thomas
authors.initials: T
authors.lastname: Seufferlein
authors.forename: Götz
authors.initials: G
authors.lastname: von Wichert
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000235:genetics / Q000378:metabolism*; D001324:Autoantigens / Q000378:metabolism; D015153:Blotting, Western; D002276:Carcinoid Tumor / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053379:Chromogranin A / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism* / Q000648:ultrastructure; D000077614:Golgi Matrix Proteins; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D011485:Protein Binding; D034622:RNA Interference; D017526:Receptor, IGF Type 1 / Q000378:metabolism
chemical_list: D001324:Autoantigens; D053379:Chromogranin A; D000077614:Golgi Matrix Proteins; C450721:Golgi complex autoantigen, 97-kDa; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D020823:ADP-Ribosylation Factor 1
keywords: ADP-ribosylation factor; Golgi apparatus; carcinoid syndrome; insulin-like growth factor 1; neuroendocrine secretion