Endothelial cell tumor growth is Ape/ref-1 dependent.

Area of Science:

• Endothelial cell biology
• Cancer research
• Oxidative stress mechanisms

Background:

• Tumor-forming endothelial cells exhibit elevated Nox-4, leading to nuclear H2O2 production.
• High levels of H2O2 are typically incompatible with cell survival, necessitating compensatory mechanisms.

Purpose of the Study:

• To identify compensatory mechanisms enabling tumor-forming endothelial cells to survive and proliferate under high oxidative stress.
• To elucidate the role of Ape-1/ref-1 (Apex-1) in endothelial cell tumor formation.

Main Methods:

• Utilized a validated mouse endothelial cell (EOMA) tumor model.
• Investigated the effect of Nox-4-derived H2O2 on DNA oxidation and Apex-1 expression.
• Assessed the impact of the Apex-1 inhibitor E3330 on tumor volume.

Main Results:

• Nox-4-derived H2O2 induces DNA oxidation, subsequently upregulating Apex-1 expression in EOMA cells.
• Apex-1 facilitates AP-1 transcription factor binding to the monocyte chemoattractant protein-1 (mcp-1) promoter, promoting tumor formation.
• Inhibition of Apex-1 with E3330 reduced tumor volume by 50%.

Conclusions:

• Nox-4 induction of Apex-1 is a critical mechanism supporting endothelial cell tumor proliferation.
• Apex-1 acts as a chaperone, maintaining transcription factors in a reduced state necessary for tumor survival.
• Targeting Apex-1 presents a potential therapeutic strategy for endothelial cell tumors.