Effects of Somatostatin Analogs and Dopamine Agonists on Insulin-Like Growth Factor 2-Induced Insulin Receptor Isoform A Activation by Gastroenteropancreatic Neuroendocrine Tumor Cells
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Publication date
2016-09-01
Authors
Van Adrichem, Roxanne C S
De Herder, Wouter W.
Kamp, Kimberly
Brugts, Michael P.
De Krijger, Ronald R.
Sprij-Mooij, Diana M.
Lamberts, Steven W J
Van Koetsveld, Peter M.
Janssen, Joseph A M J L
Hofland, Leo J.
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Document Type
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Abstract
Background: 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). Objectives: 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. Methods: 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. Results: 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). Conclusions: (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.
Keywords
Dopamine agonists, Gastroenteropancreatic neuroendocrine tumors, Human pancreatic neuroendocrine tumor cells, Insulin receptor A, Insulin-like growth factor 2, Somatostatin analogs, Endocrinology, Diabetes and Metabolism, Endocrinology, Endocrine and Autonomic Systems, Cellular and Molecular Neuroscience, Journal Article
Citation
Van Adrichem, R C S, De Herder, W W, Kamp, K, Brugts, M P, De Krijger, R R, Sprij-Mooij, D M, Lamberts, S W J, Van Koetsveld, P M, Janssen, J A M J L & Hofland, L J 2016, 'Effects of Somatostatin Analogs and Dopamine Agonists on Insulin-Like Growth Factor 2-Induced Insulin Receptor Isoform A Activation by Gastroenteropancreatic Neuroendocrine Tumor Cells', Neuroendocrinology, vol. 103, no. 6, pp. 815-825. https://doi.org/10.1159/000444280