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

Giovanni Vitale, Peter M. Van Koetsveld, Wouter W. De Herder, Katy Van Der Wansem, Joop A M J L Janssen, Annamaria Colao, Gaetano Lombardi, Steven W J Lamberts, Leo J. Hofland

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We recently demonstrated that interferon (IFN)-β has a more potent antitumor activity than IFN-α 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-α (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-α (+28%, P <0.001) and downregulated by IFN-β (-47%, P <0.001). Immunoreactive IGF-II concentration decreased in the conditioned medium during IFN-α (-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-α 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-α and 2) only IFN-β inhibits the expression of IGF-I receptor.

Original languageEnglish
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number3
Publication statusPublished - Mar 2009



  • Insulin-like growth factor-I receptor
  • Insulin-like growth factor-II
  • Neuroendocrine tumors
  • Type I interferons

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism

Cite this

Vitale, G., Van Koetsveld, P. M., De Herder, W. W., Van Der Wansem, K., Janssen, J. A. M. J. L., Colao, A., Lombardi, G., Lamberts, S. W. J., & Hofland, L. J. (2009). Effects of type I interferons on IGF-mediated autocrine/paracrine growth of human neuroendocrine tumor cells. American Journal of Physiology - Endocrinology and Metabolism, 296(3). https://doi.org/10.1152/ajpendo.90770.2008