Dual function of nitric oxide in carcinogenesis, reappraisal

Nitric oxide, a unique signalling molecule, is synthesized from L-arginine by a family of isoenzymes called nitric oxide synthase. Function of nitric oxide largely depends on the concentrations of surrounding free radicals and redox state. The local concentration of the nitric oxide defines its anti- or protumorigenic function by interacting with DNA or DNA repair enzymes and tumor suppressor gene, p53, as well. Indoleamine 2,3-dioxygenase activity is induced by interferon-gamma in many human cell types or cancer cells. Indoleamine 2,3- dioxygenase depletes locally available L- tryptophan producing cytotoxic metabolite kynurenine. Nitric oxide regulates the indoleamine 2,3-dioxygenase activity in a dose dependent-manner leading to either enhanced immune response or immune tolerance against tumor tissue. Additionally, the overproduction of nitric oxide may also trigger the cyclooxygenase-lipooxygenase pathways. Nitric oxide synthase expression correlates with cyclooxygenase-2 expression in cancer cells. On the other hand, tetrahydrobiopterin acts as the cofactor for nitric oxide synthase and stabilizes nitric oxide synthase dimers. However, tetrahydrobiopterin acts biphasically; under limited concentrations of tetrahydrobiopterin, nitric oxide generates superoxide radicals. Thus the dual action of nitric oxide and its interaction with the related compounds are of concern for their contribution in the development of carcinogenesis. In this review critical links between the nitric oxide and chronic inflammation associated carcinogenesis are summarized.