Effects of type I interferons on IGF-mediated autocrine/paracrine growth of human neuroendocrine tumor cells

被引：25

作者：

Vitale, Giovanni ^{[1
]}

van Koetsveld, Peter M. ^{[1
]}

de Herder, Wouter W. ^{[1
]}

van der Wansem, Katy ^{[1
]}

Janssen, Joop A. M. J. L. ^{[1
]}

Colao, Annamaria ^{[2
]}

Lombardi, Gaetano ^{[2
]}

Lamberts, Steven W. J. ^{[1
]}

Hofland, Leo J. ^{[1
]}

机构：

[1] Erasmus MC, Div Endocrinol, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands

[2] Univ Naples Federico II, Dept Mol & Clin Endocrinol & Oncol, Naples, Italy

来源：

AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM | 2009年 / 296卷 / 03期

关键词：

neuroendocrine tumors; type I interferons; insulin-like growth factor-II; insulin-like growth factor-I receptor; ALPHA-INTERFERON; AUTOCRINE REGULATOR; GENE-EXPRESSION; CARCINOMA-CELLS; FACTOR SYSTEM; GLIOMA-CELLS; IFN-BETA; CANCER; SECRETION; RECEPTOR;

D O I：

10.1152/ajpendo.90770.2008

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Vitale G, van Koetsveld PM, de Herder WW, van der Wansem K, Janssen JA, Colao A, Lombardi G, Lamberts SW, Hofland LJ. Effects of type I interferons on IGF-mediated autocrine/paracrine growth of human neuroendocrine tumor cells. Am J Physiol Endocrinol Metab 296: E559-E566, 2009. First published January 13, 2009; doi:10.1152/ajpendo.90770.2008.-We recently demonstrated that interferon (IFN)-beta has a more potent antitumor activity than IFN-alpha in BON cells, a neuroendocrine tumor (NET) cell line. The present study showed the role of type I IFNs in the modulation of the insulin-like growth factor (IGF) system in NETs. BON cells expressed IGF-I, IGF-II, IGF-I receptor, and insulin receptor mRNA. In addition, IGF-I and IGF-II stimulated the proliferation of BON cells and induced an inhibition of DNA fragmentation (apoptosis). As evaluated by quantitative RT-PCR, treatment with IFN-alpha (100 IU/ml) or IFN-beta (100 IU/ml) inhibited the expression of IGF-II mRNA (-42% and -65%, respectively, both P < 0.001), whereas IGF-I receptor mRNA was significantly upregulated by IFN-alpha (+28%, P < 0.001) and downregulated by IFN-beta (-47%, P < 0.001). Immunoreactive IGF-II concentration decreased in the conditioned medium during IFN-alpha (-16%, P < 0.05) and IFN-beta (-69%, P < 0.001) treatment. Additionally, IGF-I receptor bioactivity was reduced (-54%) after IFN-beta treatment. Scatchard analysis of I-125-labeled IGF-I binding to cell membrane of BON cells revealed a dramatic suppression of maximum binding capacity only in the presence of IFN-beta. Finally, the proapoptotic activity of IFN-beta was partially counteracted by the coadministration of IGF-I and IGF-II (both at 50 nM). In conclusion, these data demonstrate that the IGF system has an important role in autocrine/paracrine growth of BON cells. The more potent antitumor activity of IFN-beta compared with IFN-alpha could be explained by several effects on this system: 1) both IFNs inhibit the transcription of IGF-II, but the suppression is significantly higher after IFN-beta than IFN-alpha and 2) only IFN-beta inhibits the expression of IGF-I receptor.

引用

页码：E559 / E566

页数：8

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