AUTHOR=Alam Asim , Smith Steven C. , Gobalakrishnan Sundaresan , McGinn Mina , Yakovlev Vasily A. , Rabender Christopher S. 

TITLE=Uncoupled nitric oxide synthase activity promotes colorectal cancer progression

JOURNAL=Frontiers in Oncology

VOLUME=Volume 13 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1165326

DOI=10.3389/fonc.2023.1165326

ISSN=2234-943X

ABSTRACT=Increased levels of reactive oxygen/nitrogen species are one hallmark of chronic inflammation contributing to the activation of pro-inflammatory/proliferative pathways.  In those cancers analyzed, the tetrahydrobiopterin:dihydrobiopterin ratio is lower than that of the corresponding normal tissue leading to uncoupled nitric oxide synthase  activity and increased generation of reactive oxygen/ nitrogen species.  Previously we demonstrated that prophylactic treatment with sepiapterin, a salvage pathway precursor of tetrahydrobiopterin, prevents dextran sodium sulfate induced colitis in mice and associated azoxymethane-induced colorectal cancer. Herein we report that increasing the tetrahydrobiopterin:dihydrobiopterin ratio and recoupling nitric oxide synthase with sepiapterin in the colon cancer cell lines, HCT116 and HT29, inhibits their proliferation and enhances cell death in part by Akt/GSK-3β mediated down-regulation of β-catenin.   Therapeutic oral gavage with sepiapterin of mice bearing azoxymethane/dextran sodium sulfate induced colorectal cancer decreased metabolic uptake of [18F]-fluorodeoxyglucose and enhanced apoptosis 9-fold in these tumors. Immunohistochemical analysis of both mouse and human tissues indicated down-regulated expression of key enzymes in tetrahydrobiopterin biosynthesis in the colorectal cancer tumors.  Human stage 1 colon tumors exhibited a significant decrease in the expression of quinoid dihydropteridine reductase, a key enzyme involved in recycling tetrahydrobiopterin suggesting a potential mechanism for the reduced tetrahydrobiopterin:dihydrobiopterin ratio in these tumors. In summary, sepiapterin treatment of colorectal cancer cells increases the tetrahydrobiopterin:dihydrobiopterin ratio, recouples nitric oxide synthase, and reduces tumor growth.  We conclude that nitric oxide synthase coupling may provide a useful therapeutic target for treating patients with colorectal cancer.