生长抑素类似物和多巴胺激动剂对胃肠胰神经内分泌肿瘤细胞胰岛素样生长因子2诱导的胰岛素受体A亚型激活的影响。

Effects of Somatostatin Analogs and Dopamine Agonists on Insulin-Like Growth Factor 2-Induced Insulin Receptor Isoform A Activation by Gastroenteropancreatic Neuroendocrine Tumor Cells.

作者信息

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

机构信息

Division of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

出版信息

Neuroendocrinology. 2016;103(6):815-25. doi: 10.1159/000444280. Epub 2016 Feb 2.

DOI:10.1159/000444280

PMID:26836610

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.

摘要

背景

胃肠胰神经内分泌肿瘤（GEP-NETs）表达胰岛素样生长因子（IGF）相关因子[IGF1、IGF2；胰岛素受体（IR）-A、IR-B；IGF结合蛋白（IGFBP）1-3]以及生长抑素（SSTRs）和多巴胺D2受体（D2Rs）。

目的

（1）比较人胰腺神经内分泌肿瘤（panNET）细胞系与人类GEP-NETs中IGF相关因子的mRNA表达，以评估这些细胞作为研究GEP-NETs中IGF系统模型的实用性；（2）确定panNET细胞是否产生激活IR-A的生长因子；（3）研究生长抑素类似物（SSAs）和/或多巴胺激动剂（DAs）是否影响这些生长因子的产生。

方法

在panNET细胞（BON-1和QGP-1）和GEP-NETs中，通过定量实时PCR测量IGF相关因子的mRNA表达。在panNET细胞中，评估了SSAs奥曲肽和帕瑞肽（PAS）、DA卡麦角林（CAB）以及多巴胺抑制素BIM-23A760（均为100 nM）对IGF2 mRNA和蛋白水平（通过ELISA）以及IR-A生物活性（通过激酶受体激活试验）的影响。

结果

panNET细胞和GEP-NETs具有可比的IGF相关因子表达谱。特别是在BON-1细胞中，IGF2和IR-A表达最高。PAS + CAB抑制BON-1细胞中IGF2（-29.5±4.9%，p<0.01）和IGFBP3（-20.0±4.0%，p<0.01）的mRNA表达。在BON-1细胞中，BIM-23A760显著抑制IGF2蛋白分泌（-23.7±3.8%）。BON-1条件培养基而非QGP-1条件培养基刺激IR-A生物活性。在BON-1细胞中，BIM-23A760和PAS + CAB抑制IR-A生物活性（分别为-37.8±2.1%和-30.9±4.1%，p<0.0001）。