Effects of type I interferons on IGF-mediated autocrine/paracrine growth of human neuroendocrine tumor cells.
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 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-alpha (100 IU/ml) or IFN-beta (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-alpha (+28%, P < 0.001) and downregulated 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 (125)I-labeled 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 proapoptotic activity of IFN-beta 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-beta compared with 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 and 2) only IFN-beta inhibits the expression of IGF-I receptor.
Vitale
Giovanni
G
Department of Internal Medicine, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands.
van Koetsveld
Peter M
PM
de Herder
Wouter W
WW
van der Wansem
Katy
K
Janssen
Joop A M J L
JA
Colao
Annamaria
A
Lombardi
Gaetano
G
Lamberts
Steven W J
SW
Hofland
Leo J
LJ
D000970:Antineoplastic Agents / Q000494:pharmacology; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology*; D016899:Interferon-beta / Q000494:pharmacology*; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D019899:Paracrine Communication / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D007155:Immunologic Factors; D016898:Interferon-alpha; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D016899:Interferon-beta; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin