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

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.

• Authors: Roxanne C S van Adrichem, Wouter W de Herder, Kimberly Kamp, Michael P Brugts, Ronald R de Krijger, Diana M Sprij-Mooij, Steven W J Lamberts, Peter M van Koetsveld, Joseph A M J L Janssen, Leo J Hofland
• Journal: Neuroendocrinology (Neuroendocrinology) Vol. 103 Issue 6 Pg. 815-25 ( 2016) ISSN: 1423-0194 [Electronic] Switzerland
• PMID: 26836610 (Publication Type: Journal Article)
• Copyright: © 2016 The Author(s) Published by S. Karger AG, Basel.

Chemical References

• Antigens, CD
• Culture Media, Conditioned
• Dopamine Agonists
• IGF2 protein, human
• RNA, Messenger
• Receptors, Dopamine D2
• Receptors, Somatostatin
• Somatostatin
• Insulin-Like Growth Factor II
• INSR protein, human
• Receptor, Insulin
• TBR-760
• Dopamine

Topics

• Antigens, CD (genetics, metabolism)
• Cell Line, Tumor (chemistry)
• Culture Media, Conditioned (pharmacology)
• Dopamine (analogs & derivatives, pharmacology)
• Dopamine Agonists (pharmacology)
• Enzyme-Linked Immunosorbent Assay
• Gene Expression Regulation, Neoplastic (drug effects)
• HEK293 Cells
• Humans
• Insulin-Like Growth Factor II (metabolism)
• Intestinal Neoplasms (pathology)
• Neuroendocrine Tumors (pathology)
• Pancreatic Neoplasms (pathology)
• RNA, Messenger (metabolism)
• Receptor, Insulin (genetics, metabolism)
• Receptors, Dopamine D2 (genetics, metabolism)
• Receptors, Somatostatin (genetics, metabolism)
• Somatostatin (analogs & derivatives, pharmacology)
• Stomach Neoplasms (pathology)
• Transfection