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Am J Physiol Endocrinol Metab 296: E559-E566, 2009. First published January 13, 2009; doi:10.1152/ajpendo.90770.2008
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Effects of type I interferons on IGF-mediated autocrine/paracrine growth of human neuroendocrine tumor cells

Giovanni Vitale,1 Peter M. van Koetsveld,1 Wouter W. de Herder,1 Katy van der Wansem,1 Joop A. M. J. L. Janssen,1 Annamaria Colao,2 Gaetano Lombardi,2 Steven W. J. Lamberts,1 and Leo J. Hofland1

1Division of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands; and 2Department of Molecular and Clinical Endocrinology and Oncology, "Federico II" University of Naples, Naples, Italy

Submitted 12 September 2008 ; accepted in final form 6 January 2009

We recently demonstrated that interferon (IFN)-β 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-β (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-β (–47%, P < 0.001). Immunoreactive IGF-II concentration decreased in the conditioned medium during IFN-{alpha} (–16%, P < 0.05) and IFN-β (–69%, P < 0.001) treatment. Additionally, IGF-I receptor bioactivity was reduced (–54%) after IFN-β treatment. Scatchard analysis of 125I-labeled IGF-I binding to cell membrane of BON cells revealed a dramatic suppression of maximum binding capacity only in the presence of IFN-β. Finally, the proapoptotic activity of IFN-β 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-β 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-β than IFN-{alpha} and 2) only IFN-β inhibits the expression of IGF-I receptor.

neuroendocrine tumors; type I interferons; insulin-like growth factor-II; insulin-like growth factor-I receptor


Address for reprint requests and other correspondence: L. J. Hofland, Dept. of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, Rm. EE 530b, Dr. Molewaterplein 50, 3015 GE Rotterdam, the Netherlands (e-mail: l.hofland{at}erasmsumc.nl)






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