Vascular endothelial growth factor effects on nuclear factor-κb activation in hematopoietic progenitor cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2001-03, Vol.61 (5), p.2015-2021
• Main Authors: DIKOV, Mikhail M, OYAMA, Tsunehiro, GABRILOVICH, Dmitry I, CARBONE, David P, CHENG, Pingyan, TAKAHASHI, Takamune, TAKAHASHI, Keiko, SEPETAVEC, Tanya, EDWARDS, Byard, ADACHI, Yasushi, NADAF, Sorena, DANIEL, Thomas
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Fundamental and applied biological sciences. Psychology; Molecular and cellular biology; vascular endothelial growth factor
• ISSN: 0008-5472; 1538-7445

Vascular endothelial growth factor (VEGF) inhibits of the activation of transcription factor nuclear factor- Kappa B (NF- Kappa B) in hematopoietic progenitor cells (HPCs), and this is associated with alterations in the development of multiple lineages of hematopoietic cells and defective immune induction in tumor-bearing animals. Antibodies to VEGF have been shown to abrogate this effect. The mechanism by which VEGF antagonizes the induction of NF- Kappa B was investigated in this study. Using supershift electrophoretic mobility shift analysis, we found that although tumor necrosis factor alpha (TNF- alpha ) induced the nuclear translocation and DNA binding of p65-containing complexes, VEGF alone induced nuclear translocation and DNA binding of the complexes containing RelB. These results were confirmed by immunofluorescence confocal microscopy. VEGF effectively blocked TNF- alpha -induced NF- Kappa B activation in HPCs from RelB super(-/-) mice, however, similar to the effect observed in HPCs obtained from RelB super(+/-) and RelB super(+/+) mice. This suggests that RelB is not required for VEGF to inhibit NF- Kappa B activation. However, although TNF- alpha induced rapid activation of I Kappa B kinase (IKK) as expected, this activity was substantially reduced in the presence of VEGF. This decreased IKK activation correlated with the inhibition of-I Kappa B alpha phosphorylation and degradation of I Kappa B alpha and I Kappa Bc in HPCs. VEGF alone, however, did not have any effect on phosphorylation of I Kappa B alpha or degradation of I Kappa B alpha and other inhibitory molecules I Kappa B beta , I Kappa Bc, or Bcl-3. SU5416, a potent inhibitor of the VEGF receptor 1 (VEGFR1) and VEGFR2 receptor tyrosine kinases, did not abolish the inhibitory effect of VEGF, indicating that the VEGF effect is mediated by a mechanism unrelated to VEGFR1 or VEGFR2 tyrosine kinase activity. Thus, VEGF appears to inhibit TNF- alpha -induced NF- Kappa B activation by VEGFR kinase-independent inhibition of IKK. Therapeutic strategies aimed at overcoming VEGF-mediated defects in immune induction in tumor-bearing hosts will need to target this kinase-independent pathway.