We recently demonstrated that interferon (IFN)- has a more potent antitumor activity than IFN- in BON cells, a neuroendocrine tumor (NET) cell line. The present study showed the role of type I IFNs in the modulation of 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- (100 IU/ml) or IFN- (100 IU/ml) inhibited the expression of IGF-II mRNA (-42%, -65%, respectively, both p<0.001), while IGF-I receptor mRNA was significantly up-regulated by IFN- (+28%, p<0.001) and down-regulated by IFN- (-47%, p<0.001). Immunoreactive IGF-II concentration decreased in the conditioned medium during IFN- (-16%, p<0.05) and IFN- (-69%, p<0.001) treatment. Additionally, IGF-I receptor bioactivity was reduced (-54%) after IFN- treatment. Scatchard analysis of 125I-IGF-I binding to cell membrane of BON cells revealed a dramatic suppression of maximum binding capacity only in the presence of IFN-. Finally, the pro-apoptotic activity of IFN- was partially counteracted by the co-administration of IGF-I and IGF-II (both at 50nM). 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- compared to IFN- 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- than IFN-; 2) only IFN- inhibits the expression of IGF-I receptor.