Cell-specific but p53-independent regulation of vascular endothelial growth factor expression by interferons in human glioblastoma cells.
Vascular endothelial growth factor (VEGF) is a key mediator of tumor angiogenesis. Interferons (IFNs) have been widely used in the treatment of malignant or recurrent gliomas with only marginal benefit. The association between IFNs and VEGF expression remains unclear and should be an intensively investigated subject. The present study therefore examined the effects of different types of IFNs on VEGF expression in human T98G, A172 and U251 glioblastoma cells by quantitative RT-PCR and ELISA. Both type I (alpha, beta) and type II (gamma) IFNs upregulated VEGF expression in a cell-specific but p53-independent manner. Actinomycin D experiments demonstrated that IFNs did not alter VEGF mRNA stability. In contrast, induction of VEGF mRNA by IFNs was blocked by the protein synthesis inhibitor cycloheximide. Interestingly, cycloheximide also blocked IFN-induced activation of the p44/p42 mitogen-activated protein kinase, which was partially required for induction of VEGF by IFNs. These findings suggest that VEGF might be an indirect target gene of IFNs, and might provide insights into therapeutic applications of IFNs against angiogenesis-dependent tumors.
Yao
Yongxue
Y
Department of Neurosurgery, University of Fukui, Matsuoka, Fukui, 910-1193, Japan. yonyao@iupui.edu
Kubota
Toshihiko
T
Sato
Kazufumi
K
Takeuchi
Hiroaki
H
Handa
Yuji
Y
Matsukawa
Shigeru
S
D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000187:drug effects*
D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D003609:Dactinomycin; D007372:Interferons; D003513:Cycloheximide; D020928:Mitogen-Activated Protein Kinases