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.
Rosewicz
Stefan
S
Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
Detjen
Katharina
K
Scholz
Arne
A
von Marschall
Z
Z
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