title: Effects of Somatostatin Analogs and Dopamine Agonists on Insulin-Like Growth Factor 2-Induced Insulin Receptor Isoform A Activation by Gastroenteropancreatic Neuroendocrine Tumor Cells.
abstract: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) express insulin-like growth factor (IGF)-related factors [IGF1, IGF2; insulin receptor (IR)-A, IR-B; IGF-binding protein (IGFBP) 1-3] as well as somatostatin (SSTRs) and dopamine D2 receptors (D2Rs).
  
  
  
  To (1) compare mRNA expression of IGF-related factors in human pancreatic NET (panNET) cell lines with that in human GEP-NETs to evaluate the usefulness of these cells as a model for studying the IGF system in GEP-NETs, (2) determine whether panNET cells produce growth factors that activate IR-A, and (3) investigate whether somatostatin analogs (SSAs) and/or dopamine agonists (DAs) influence the production of these growth factors.
  
  
  
  In panNET cells (BON-1 and QGP-1) and GEP-NETs, mRNA expression of IGF-related factors was measured by quantitative real-time PCR. Effects of the SSAs octreotide and pasireotide (PAS), the DA cabergoline (CAB), and the dopastatin BIM-23A760 (all 100 nM) were evaluated at the IGF2 mRNA and protein level (by ELISA) and regarding IR-A bioactivity (by kinase receptor activation assay) in panNET cells.
  
  
  
  panNET cells and GEP-NETs had comparable expression profiles of IGF-related factors. Especially in BON-1 cells, IGF2 and IR-A were most highly expressed. PAS + CAB inhibited IGF2 (-29.5 ± 4.9%, p < 0.01) and IGFBP3 (-20.0 ± 4.0%, p < 0.01) mRNA expression in BON-1 cells. In BON-1 cells, IGF2 protein secretion was significantly inhibited with BIM-23A760 (-23.7 ± 3.8%). BON-1- but not QGP-1- conditioned medium stimulated IR-A bioactivity. In BON-1 cells, IR-A bioactivity was inhibited by BIM-23A760 and PAS + CAB (-37.8 ± 2.1% and -30.9 ± 4.1%, respectively, p < 0.0001).
  
  
  
  (1) The BON-1 cell line is a representative model for studying the IGF system in GEP-NETs, (2) BON-1 cells produce growth factors (IGF2) activating IR-A, and (3) combined SSTR and D2R targeting with PAS + CAB and BIM-23A760 suppresses IGF2-induced IR-A activation.
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Roxanne C S
authors.initials: RC
authors.lastname: van Adrichem
authors.forename: Wouter W
authors.initials: WW
authors.lastname: de Herder
authors.forename: Kimberly
authors.initials: K
authors.lastname: Kamp
authors.forename: Michael P
authors.initials: MP
authors.lastname: Brugts
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
authors.forename: Diana M
authors.initials: DM
authors.lastname: Sprij-Mooij
authors.forename: Steven W J
authors.initials: SW
authors.lastname: Lamberts
authors.forename: Peter M
authors.initials: PM
authors.lastname: van Koetsveld
authors.forename: Joseph A M J L
authors.initials: JA
authors.lastname: Janssen
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Hofland
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000737:chemistry; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004298:Dopamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D007414:Intestinal Neoplasms / Q000473:pathology; D018358:Neuroendocrine Tumors / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000235:genetics / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000473:pathology; D014162:Transfection
chemical_list: D015703:Antigens, CD; D017077:Culture Media, Conditioned; D018491:Dopamine Agonists; C035170:IGF2 protein, human; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D017481:Receptors, Somatostatin; D013004:Somatostatin; D007335:Insulin-Like Growth Factor II; C435941:INSR protein, human; D011972:Receptor, Insulin; C531242:TBR-760; D004298:Dopamine