The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression.
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.


CONCLUSIONS
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.
Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia.
Christopher S
CS
Rabender
Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia.
Asim
A
Alam
Department of Radiology and Center for Molecular Imaging, Virginia Commonwealth University, Richmond, Virginia.
Gobalakrishnan
G
Sundaresan
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson, Houston, Texas.
Robert J
RJ
Cardnell
Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia.
Vasily A
VA
Yakovlev
Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia.
Nitai D
ND
Mukhopadhyay
Department of Radiation Oncology, New York Methodist Hospital, Weill Cornell Medical College, Brooklyn, New York.
Paul
P
Graves
Department of Radiology and Center for Molecular Imaging, Virginia Commonwealth University, Richmond, Virginia.
Jamal
J
Zweit
Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia. rmikkels@vcu.edu.
Ross B
RB
Mikkelsen
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D045744:Cell Line, Tumor; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D018450:Disease Progression; D064593:Heterografts; D006801:Humans; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000378:metabolism; D011622:Pterins / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D016328:NF-kappa B; D011622:Pterins; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin; D013481:Superoxides; D030421:Peroxynitrous Acid; D001708:Biopterins; C017226:7,8-dihydrobiopterin; C016727:sepiapterin; D019001:Nitric Oxide Synthase; D017869:Cyclic GMP-Dependent Protein Kinases; C003402:sapropterin