| First Author | Rabender CS | Year | 2015 |
| Journal | Mol Cancer Res | Volume | 13 |
| Issue | 6 | Pages | 1034-43 |
| PubMed ID | 25724429 | Mgi Jnum | J:222592 |
| Mgi Id | MGI:5644907 | Doi | 10.1158/1541-7786.MCR-15-0057-T |
| Citation | Rabender CS, et al. (2015) The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression. Mol Cancer Res 13(6):1034-43 |
| abstractText | 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 beta-catenin expression, and TCF4 promoter activity, and reduced NF-kappaB 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. |
