IkappaBalphaM suppresses angiogenesis and tumorigenesis promoted by a constitutively active mutant EGFR in human glioma cells.
Human glioma cell lines (G36DeltaEGFR and IN500DeltaEGFR) have been shown to display an enhanced tumorigenic phenotype, when transfected with a constitutively active form of the epidermal growth factor receptor (DeltaEGFR). These cells were transfected with a mutant IkappaBalpha (IkappaBalphaM) that is resistant to phosphorylation and degradation, and hence blocks NF-kappaB activity. Recently, EGFR has been shown to increase the activity of NF-kappaB and to induce angiogenesis. In this report, we asked if IkappaBalphaM gene transfer into human glioma cell lines would inhibit tumorigenicity and angiogenesis in glioma. IkappaBalphaM inhibited in vitro and in vivo expression of vascular endothelial growth factor (VEGF) and interleukin 8 (IL-8). Human glioma xenografts treated with IkappaBalphaM gene transfer exhibited significantly decreased angiogenesis both in an orthotopic and in an ectopic model. The decreased expression of VEGF and IL-8 directly correlated with decreased tumorigenicity, and tumor vascularization. Taken in combination, these results provide strong evidence of IkappaBalphaM's role in regulating glioma angiogenesis even in the presence of constitutive EGFR activation.
Wu
Jian Liang
JL
Department of Neurosurgery, Oita University, School of Medicine, 1-1, Idaigaoka, Hasama-machi, Oita, Japan.
Abe
Tatsuya
T
Inoue
Ryo
R
Fujiki
Minoru
M
Kobayashi
Hidenori
H
D000818:Animals; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005169:Factor VIII / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000378:metabolism / Q000517:prevention & control*; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000627:therapeutic use*; D007150:Immunohistochemistry / Q000379:methods; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude / Q000502:physiology; D016296:Mutagenesis / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors; D014162:Transfection / Q000379:methods; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020672:I-kappa B Proteins; D016209:Interleukin-8; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D000072000:NF-KappaB Inhibitor alpha; D005169:Factor VIII; D066246:ErbB Receptors