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NADPH oxidase 1 plays a critical mediating role in oncogenic Ras-induced vascular endothelial growth factor

D Komatsu1, M Kato, J Nakayama

  • 1Department of Molecular Biology and Biochemistry, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan.

Oncogene
|May 6, 2008
PubMed

Insights

Nox1 enzyme activity is crucial for Ras-induced vascular endothelial growth factor (VEGF) production and tumor angiogenesis. Inhibiting Nox1 reduces VEGF synthesis and tumor neovascularization, highlighting Nox1

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Reactive oxygen species (ROS)-generating enzyme Nox1 plays a role in oncogenic Ras transformation.
  • The involvement of Nox1 in Ras-induced upregulation of vascular endothelial growth factor (VEGF), a key factor in tumor angiogenesis, is not well-defined.

Purpose of the Study:

  • To investigate the role of Nox1 in Ras-induced VEGF production and tumor angiogenesis.
  • To elucidate the molecular mechanisms by which Nox1 influences VEGF expression and signaling.

Main Methods:

  • Utilized Nox1 small-interference RNAs (siRNAs) and diphenylene iodonium (DPI) to inhibit Nox1 activity in K-Ras transformed normal rat kidney (KNRK) cells.
  • Assessed VEGF protein and mRNA synthesis, Sp1 phosphorylation, and Sp1 binding to the VEGF promoter.
  • Evaluated neovascularization in tumors derived from Nox1siRNA-transfected KNRK cells.
  • Confirmed findings in human colon cancer CaCO-2 cells.

Main Results:

  • Ablation of Nox1 activity significantly inhibited VEGF protein and mRNA synthesis in KNRK cells.
  • Nox1 inhibition suppressed extracellular signal-regulated kinase (ERK)-dependent phosphorylation of Sp1 and its binding to the VEGF promoter.
  • Tumors from Nox1siRNA-transfected cells exhibited markedly decreased neovascularization.
  • Nox1 activity was essential for VEGF production in both KNRK and CaCO-2 cells.

Conclusions:

  • Nox1 mediates oncogenic Ras-induced upregulation of VEGF and angiogenesis.
  • Nox1 activates Sp1 through a Ras-ERK-dependent pathway, leading to increased VEGF expression.
  • Nox1 acts in concert with other effectors within the Ras network to regulate VEGF, rather than being solely sufficient.

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