We recently demonstrated that interferon (IFN)-beta 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 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-alphaalpha (100 IU/ml) or IFN-beta (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-alphaalpha (+28%, p<0.001) and down-regulated by IFN-beta (-47%, p<0.001). Immunoreactive IGF-II concentration decreased in the conditioned medium during IFN-alpha (-16%, p<0.05) and IFN-beta (-69%, p<0.001) treatment. Additionally, IGF-I receptor bioactivity was reduced (-54%) after IFN-beta 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-beta. Finally, the pro-apoptotic activity of IFN-beta 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-beta compared to 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-beta than IFN-alpha; 2) only IFN-beta inhibits the expression of IGF-I receptor. Key words: neuroendocrine tumors, type I interferons, IGF-II, IGF-I receptor.
Effects of type I interferons on IGF-mediated autocrine/paracrine growth of human neuroendocrine tumor cells / G., Vitale; P. M., van Koetsveld; W. W., de Herder; K., van der Wansem; J. A., Janssen; Colao, Annamaria; Lombardi, Gaetano; S. W., Lamberts; L. J., Hofland. - In: AMERICAN JOURNAL OF PHYSIOLOGY: ENDOCRINOLOGY AND METABOLISM. - ISSN 0193-1849. - ELETTRONICO. - 296:(2009), pp. 559-566.
Effects of type I interferons on IGF-mediated autocrine/paracrine growth of human neuroendocrine tumor cells
COLAO, ANNAMARIA;LOMBARDI, GAETANO;
2009
Abstract
We recently demonstrated that interferon (IFN)-beta 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 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-alphaalpha (100 IU/ml) or IFN-beta (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-alphaalpha (+28%, p<0.001) and down-regulated by IFN-beta (-47%, p<0.001). Immunoreactive IGF-II concentration decreased in the conditioned medium during IFN-alpha (-16%, p<0.05) and IFN-beta (-69%, p<0.001) treatment. Additionally, IGF-I receptor bioactivity was reduced (-54%) after IFN-beta 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-beta. Finally, the pro-apoptotic activity of IFN-beta 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-beta compared to 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-beta than IFN-alpha; 2) only IFN-beta inhibits the expression of IGF-I receptor. Key words: neuroendocrine tumors, type I interferons, IGF-II, IGF-I receptor.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
