Tetrahydrobiopterin (BH4) is known to be an essential cofactor for the aromatic amino acid hydroxylases, which are involved in the production of neurotransmitters, and for nitric oxide (NO) synthase. In the present study, we report that sepiapterin, the more stable form of the BH4 precursor, modulates ovarian cancer cell proliferation and migration by NO-dependent and -independent mechanisms. Sepiapterin induction of cell proliferation and migration in SKOV-3 cells is accompanied by ERK, Akt and p70S6K activation. These stimulatory effects of sepiapterin are reversed by pretreatment with NO synthase inhibitor. We also show that sepiapterin significantly inhibits vascular endothelial growth factor-A (VEGF-A)-stimulated cell proliferation and migration. Pretreatment with NO synthase inhibitor does not alter the ability of sepiapterin to inhibit VEGF-A-induced cell proliferation and migration, indicating that the suppressive effects of sepiapterin on VEGF-A-induced responses are mediated by a NO-independent mechanism. Finally, we demonstrate that sepiapterin markedly suppresses VEGF-A-induced p70S6K phosphorylation and VEGFR-2 expression, resulting in inhibition of VEGF-A-induced cell proliferation and migration. Collectively, these findings represent a biphasic effect of sepiapterin on cellular fates, depending on the presence of growth factors, and support further development and evaluation of sepiapterin for the treatment of cancers overexpressing VEGFR-2.

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