Abstract | UNLABELLED: Here, evidence suggests that nitric oxide synthases (NOS) of tumor cells, in contrast with normal tissues, synthesize predominantly superoxide and peroxynitrite. Based on high-performance liquid chromatography analysis, the underlying mechanism for this uncoupling is a reduced tetrahydrobiopterin: dihydrobiopterin ratio (BH4:BH2) found in breast, colorectal, epidermoid, and head and neck tumors compared with normal tissues. Increasing BH4:BH2 and reconstitution of coupled NOS activity in breast cancer cells with the BH4 salvage pathway precursor, sepiapterin, causes significant shifts in downstream signaling, including increased cGMP-dependent protein kinase (PKG) activity, decreased β- catenin expression, and TCF4 promoter activity, and reduced NF-κB promoter activity. Sepiapterin inhibited breast tumor cell growth in vitro and in vivo as measured by a clonogenic assay, Ki67 staining, and 2[18F]fluoro- 2-deoxy-D-glucose- deoxyglucose positron emission tomography (FDG-PET). In summary, using diverse tumor types, it is demonstrated that the BH4:BH2 ratio is lower in tumor tissues and, as a consequence, NOS activity generates more peroxynitrite and superoxide anion than nitric oxide, resulting in important tumor growth-promoting and antiapoptotic signaling properties. IMPLICATIONS: The synthetic BH4, Kuvan, is used to elevate BH4:BH2 in some phenylketonuria patients and to treat diseases associated with endothelial dysfunction, suggesting a novel, testable approach for correcting an abnormality of tumor metabolism to control tumor growth.
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Authors | Christopher S Rabender, Asim Alam, Gobalakrishnan Sundaresan, Robert J Cardnell, Vasily A Yakovlev, Nitai D Mukhopadhyay, Paul Graves, Jamal Zweit, Ross B Mikkelsen |
Journal | Molecular cancer research : MCR
(Mol Cancer Res)
Vol. 13
Issue 6
Pg. 1034-43
(Jun 2015)
ISSN: 1557-3125 [Electronic] United States |
PMID | 25724429
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | ©2015 American Association for Cancer Research. |
Chemical References |
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
- NF-kappa B
- Pterins
- TCF4 protein, human
- Transcription Factor 4
- Transcription Factors
- beta Catenin
- Superoxides
- Peroxynitrous Acid
- Biopterin
- 7,8-dihydrobiopterin
- sepiapterin
- Nitric Oxide Synthase
- Cyclic GMP-Dependent Protein Kinases
- sapropterin
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Topics |
- Animals
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
(metabolism)
- Biopterin
(analogs & derivatives, metabolism)
- Cell Line, Tumor
- Cyclic GMP-Dependent Protein Kinases
(metabolism)
- Disease Progression
- Heterografts
- Humans
- Mice, Nude
- NF-kappa B
(metabolism)
- Neoplasms
(metabolism, pathology)
- Nitric Oxide Synthase
(metabolism)
- Peroxynitrous Acid
(metabolism)
- Pterins
(metabolism)
- Superoxides
(metabolism)
- Transcription Factor 4
- Transcription Factors
(metabolism)
- beta Catenin
(metabolism)
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