The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression.

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.

• 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)
• 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

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)