Interferon-alpha: regulatory effects on cell cycle and angiogenesis.
In the current study, we investigated the effects of interferon-alpha (IFN-alpha) on proliferation and angiogenesis in neuroendocrine tumor disease. Using a panel of human neuroendocrine tumor cell lines, we confirmed functionally active IFN-alpha signaling by STAT activation and nuclear translocation as well as transactivation. IFN-alpha results in anchorage-dependent and -independent growth inhibition due to a delayed progression from S-phase to G2 phase of the cell cycle. This was due to substantial reduction in cellular cyclin B levels resulting in the inhibition of Cdc2 kinase activity. In parallel to growth inhibition, we observed a profound inhibition of VEGF gene transcription by IFN-alpha in human neuroendocrine tumor cells due to an Sp1/Sp3-dependent inhibition of VEGF promoter activity. Treatment of neuroendocrine tumors with IFN-alpha in nude mice resulted in growth inhibition and inhibition of angiogenesis. Furthermore, treatment of neuroendocrine tumor patients with IFN-alpha resulted in decreased VEGF expression as well as tumor angiogenesis in liver metastases. In summary, IFN-alpha acts via direct antiproliferative effects as well as inhibition of tumor angiogenesis mediated by suppression of VEGF gene expression in neuroendocrine tumor disease.
Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
Stefan
S
Rosewicz
Katharina
K
Detjen
Arne
A
Scholz
Z
Z
von Marschall
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western / Q000379:methods; D002452:Cell Count / Q000379:methods; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D053613:Janus Kinase 1; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017471:Receptors, Interferon / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000378:metabolism; D053634:TYK2 Kinase; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000235:genetics
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007136:Immunoglobulins; D016898:Interferon-alpha; D017471:Receptors, Interferon; D017481:Receptors, Somatostatin; C090698:SP1 antigen; D042461:Vascular Endothelial Growth Factor A; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D053634:TYK2 Kinase; C070139:TYK2 protein, human