Blockade of NF-kappaB Activity in Human Prostate Cancer Cells Is Associated With Suppression of Angiogenesis, Invasion, and Metastasis

Oncogene. 2001 Jul 12;20(31):4188-97. doi: 10.1038/sj.onc.1204535.

Abstract

Since the NF-kappaB/relA transcription factor is constitutively activated in human prostate cancer cells, we determined whether blocking NF-kappaB/relA activity in human prostate cancer cells affected their angiogenesis, growth, and metastasis in an orthotopic nude mouse model. Highly metastatic PC-3M human prostate cancer cells were transfected with a mutated IkappaBalpha (IkappaBalphaM), which blocks NF-kappaB activity. Parental (PC-3M), control vector-transfected (PC-3M-Neo), and IkappaBalphaM-transfected (PC-3M-IkappaBalphaM) cells were injected into the prostate gland of nude mice. PC-3M and PC-3M-Neo cells produced rapidly growing tumors and regional lymph node metastasis, whereas PC-3M-IkappaBalphaM cells produced slow growing tumors with low metastatic potential. NF-kappaB signaling blockade significantly inhibited in vitro and in vivo expression of three major proangiogenic molecules, VEGF, IL-8, and MMP-9, and hence decreased neoplastic angiogenesis. Inhibition of NF-kappaB activity in PC-3M cells also resulted in the downregulation of MMP-9 mRNA and collagenase activity, resulting in decreased invasion through Matrigel. Collectively, these data suggest that blockade of NF-kappaB activity in PC-3M cells inhibits angiogenesis, invasion, and metastasis.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • Cell Division
  • DNA Primers
  • DNA-Binding Proteins / genetics
  • Endothelial Growth Factors / metabolism
  • Genetic Vectors
  • Humans
  • I-kappa B Proteins*
  • Immunohistochemistry
  • Lymphokines / metabolism
  • Male
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Neoplasm Invasiveness*
  • Neoplasm Metastasis*
  • Neovascularization, Pathologic*
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Transfection
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • DNA Primers
  • DNA-Binding Proteins
  • Endothelial Growth Factors
  • I-kappa B Proteins
  • Lymphokines
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • NF-KappaB Inhibitor alpha
  • Matrix Metalloproteinase 9