Journal
ONCOLOGY REPORTS
Volume 26, Issue 4, Pages 861-867Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/or.2011.1335
Keywords
tetrahydrobiopterin; sepiapterin; vascular endothelial growth factor-A; ovarian cancer; nitric oxide
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Funding
- Ministry of Education, Science Technology (MEST) [2009-0065896]
- Brain Korea 21 program
- National Research Foundation of Korea [20090305132707, 2009-0065896] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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 p70(S6K) 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 p70(S6K) 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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