Uncoupled nitric oxide synthase activity promotes colorectal cancer progression

Abstract

Increased levels of reactive oxygen/nitrogen species are one hallmark of chronic inflammation contributing to the activation of pro-inflammatory/proliferative pathways. In the cancers analyzed, the tetrahydrobiopterin:dihydrobiopterin ratio is lower than that of the corresponding normal tissue, leading to an 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, inhibit their proliferation and enhance cell death, in part, by Akt/GSK-3β–mediated downregulation 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 nine-fold in these tumors. Immunohistochemical analysis of both mouse and human tissues indicated downregulated 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.

Pakis Kinca (Nephrolepis Cordifolia (L) C. Presl) Sebagai Inhibitor Nitric Oxide Synthase

“…Struktur kami menunjukkan bahwa plastisitas residu diferensial dapat dieksploitasi untuk perubahan konformasi yang menciptakan kantong spesifisitas baru yang sesuai untuk desain inhibitor spesifik isozim [12]. Pengikatan ini memiliki implikasi yang menarik bagi penemuan obat, dan menunjukkan bahwa kristalografi sinar-X sangat penting untuk mengungkap perbedaan halus namun penting dalam plastisitas residu antara isozim yang berkerabat dekat (misalnya iNOS vs. eNOS) atau antara enzim homolog dari organisme berbeda [13]. Peran penting residu cangkang kedua dan ketiga dalam menentukan plastisitas residu cangkang pertama yang dilestarikan akan menambah tantangan yang ada dalam memodelkan protein yang diinduksi secara akurat.…”

NOS2 and COX-2 Co-Expression Promotes Cancer Progression: A Potential Target for Developing Agents to Prevent or Treat Highly Aggressive Breast Cancer

“…This free radical is implicated in driving three key factors associated with unfavorable clinical outcomes in cancer: metastasis, resistance to chemo and radiotherapy, and immune suppression [ 8 , 37 , 38 ]. While some studies suggest positive effects of NO [ 39 , 40 , 41 ], the majority link high NOS2 expression to poor survival across a spectrum of hematological and solid tumors, including breast [ 8 ], pancreatic [ 42 ], nasopharyngeal carcinoma [ 43 ], colorectal [ 44 , 45 ], gastric [ 46 ], esophageal [ 47 ], prostate [ 48 ], melanoma [ 49 ], Hodgkin’s lymphoma [ 50 ], ovarian [ 51 ], squamous cell carcinoma [ 52 ], renal cell carcinoma [ 53 ], glioma [ 54 ], chondrosarcomas [ 55 ], Barrett’s esophageal adenocarcinoma [ 56 ], and in HCV-infected liver cancer patients [ 57 ].…”