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

By G. Vitale, P.M. Van Koetsveld, W.W. De Herder, K. Van Der Wansem, J.A.M.L. Janssen, A. Colao, G. Lombardi, S.W.J. Lamberts and L.J. Hofland

Abstract

We recently demonstrated that interferon (IFN)-\u3b2 has a more potent antitumor activity than IFN-\u3b1 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-\u3b1 (100 IU/ml) or IFN-\u3b2 (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-\u3b1 (+28%, P < 0.001) and downregulated by IFN-\u3b2 (-47%, P < 0.001). Immunoreactive IGF-II concentration decreased in the conditioned medium during IFN-\u3b1 (-16%, P < 0.05) and IFN-\u3b2 (-69%, P < 0.001) treatment. Additionally, IGF-I receptor bioactivity was reduced (-54%) after IFN-\u3b2 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-\u3b2. Finally, the proapoptotic activity of IFN-\u3b2 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-\u3b2 compared with IFN-\u3b1 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-\u3b2 than IFN-\u3b1 and 2) only IFN-\u3b2 inhibits the expression of IGF-I receptor

Topics: Insulin-like growth factor-I receptor, Insulin-like growth factor-II, Neuroendocrine tumors, Type I interferons, Settore MED/13 - Endocrinologia
Publisher: 'American Physiological Society'
Year: 2009
DOI identifier: 10.1152/ajpendo.90770.2008
OAI identifier: oai:air.unimi.it:2434/70743
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