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

Research output: Contribution to journalArticlepeer-review


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


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