Blockade of nuclear factor-kappaB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8.
We determined whether blockade of nuclear factor (NF)-kappaB/relA activity in human ovarian cancer cells can suppress angiogenesis and growth in an orthotopic nude mouse model. The human ovarian cancer cells SKOV3ip.1 and HEY-A8 were transfected with a mutated IkappaBalpha (IkappaBalphaM), ie., resistant to phosphorylation and degradation, and hence blocks NF-kappaB activity. NF-kappaB signaling blockade significantly inhibited in vitro and in vivo expression of two major proangiogenic molecules, vascular endothelial growth factor and interleukin 8, in cultured cells and in cells implanted into the peritoneal cavity of nude mice. The decreased expression of vascular endothelial growth factor and interleukin 8 directly correlated with decreased tumorigenicity, decreased vascularization of lesions, decreased formation of malignant ascites, and prolonged survival of mice. These findings suggest that inhibition of NF-kappaB/relA activity in ovarian cancer cells can suppress angiogenesis and progressive growth.
Huang
S
S
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Robinson
J B
JB
Deguzman
A
A
Bucana
C D
CD
Fidler
I J
IJ
D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000517:prevention & control; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D023041:Xenograft Model Antitumor Assays
D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D020672:I-kappa B Proteins; D016209:Interleukin-8; D008222:Lymphokines; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000072000:NF-KappaB Inhibitor alpha