Immune Netw.  2003 Mar;3(1):38-46. 10.4110/in.2003.3.1.38.

Role of Nuclear Factor (NF)-kappaB Activation in Tumor Growth and Metastasis

• Ko HM
• Choi JH
• Ra MS
• Im SY

• KMID: 2167969
• DOI: http://doi.org/10.4110/in.2003.3.1.38

Abstract

BACKGROUND
Platelet-activating factor (PAF) induces nuclear factor (NF)-kappaB activation and angiogenesis and increases tumor growth and pulmonary tumor metastasis in vivo. The role of NF-kappaB activation in PAF-induced angiogenesis in a mouse model of Matrigel implantation, and in PAF-mediated pulmonary tumor metastasis were investigated. METHODS: Angiogenesis using Matrigel and experimental pulmonary tumor metastasis were tested in a mouse model. Electrophoretic mobility shift assay was done for the assessment of NF-kappaB translocation to the nucleus. Expression of angiogenic factors, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1alpha, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) were tested by RT-PCR and ELISA. RESULTS: PAF induced a dose- and time-dependent angiogenic response. PAF-induced angiogenesis was significantly blocked by PAF antagonist, CV6209, and inhibitors of NF-kappaB expression or action, including antisense oligonucleotides to p65 subunit of NF-kappaB (p65 AS) and antioxidants such as alpha-tocopherol and N-acetyl-L-cysteine. In vitro, PAF activated the transcription factor, NF-kappaB and induced mRNA expression of TNF-alpha, IL-1alpha, bFGF, VEGF, and its receptor, KDR. The PAF-induced expression of the above mentioned factors was inhibited by p65 AS or antioxidants. Also, protein synthesis of VEGF was increased by PAF and inhibited by p65 AS or antioxidants. The angiogenic effect of PAF was blocked when anti-VEGF antibodies was treated or antibodies against TNF-alpha, IL-1alpha, and bFGF was co-administrated, but not by antibodies against TNF-alpha, IL-1alpha, and bFGF each alone. PAF-augmented pulmonary tumor metastasis was inhibited by p65 AS or antioxidants. CONCLUSION: These data indicate that PAF increases angiogenesis and pulmonary tumor metastasis through NF-kappaB activation and expression of NF-kappaB-dependent angiogenic factors.

Keyword

Nuclear factor (NF)-kappaB; platelet-activating factor (PAF); angiogenesis vascular endothelial growth factor (VEGF)

MeSH Terms

Acetylcysteine
alpha-Tocopherol
Angiogenesis Inducing Agents
Animals
Antibodies
Antioxidants
Electrophoretic Mobility Shift Assay
Enzyme-Linked Immunosorbent Assay
Fibroblast Growth Factor 2
Interleukins
Mice
Neoplasm Metastasis*
NF-kappa B
Oligonucleotides, Antisense
RNA, Messenger
Transcription Factors
Tumor Necrosis Factor-alpha
Vascular Endothelial Growth Factor A
Acetylcysteine
Angiogenesis Inducing Agents
Antibodies
Antioxidants
Fibroblast Growth Factor 2
Interleukins
NF-kappa B
Oligonucleotides, Antisense
RNA, Messenger
Transcription Factors
Tumor Necrosis Factor-alpha
Vascular Endothelial Growth Factor A
alpha-Tocopherol