Neopterin as a Stimulator of Vascular Endothelial Growth Factor and Erythropoietin Gene Expression in an Ovarian Carcinoma Cell Line

Increases in serum neopterin concentrations are a regular finding in patients with ovarian cancer. The strong correlation between neopterin and tumor progression might be explained by a direct influence of the pteridine compound on tumor cell growth. In the present study we investigated whether neopterin affects the production of the angiogenic promotors vascular endothelial growth factor (VEGF) and erythropoietin (EPO) in the human ovarian carcinoma cell line OVCAR-3. VEGF and EPO gene expression were detected via RT-PCR. and a possible involvement of hypoxiainducible factor-1 was assessed by electrophoretic mobility shift assays. Neopterin amplified the hypoxia-induced VEGF and EPO gene expression as well as protein synthesis in a concentration-dependent manner. In addition, generation of both VEGF and EPO could be detected following incubation of cells with neopterin under normoxic conditions, too. Neopterin-induced synthesis of VEGF and EPO was preceeded by a stimulation of hypoxiainducible factor-1 uptake into the nucleus of OVCAR-3 cells. From these data we conclude that neopterin acts as a mediator of angiogenesis. Stimulation of VEGF and EPO generation in ovarian carcinoma cells may promote vascularization of the malignant tissue and thus tumor growth and development.