Deciphering The Complex Biological Interactions Of Nitric Oxide In Cancer

NO^• is a free radical and is involved in a number of critical physiological processes including vasodilation, neurotransmission, immune regulation and inflammation. There are convincing evidence suggesting a role of NO^• in the development and progression of different cancer types. However, the role of NO^• in tumorigenesis is highly complex and both pro- and anti-neoplastic functions have been reported, which largely depends on the amount of NO^•, cell types, cellular microenvironment, its interaction with other reactive species and presence of metals. An interesting interaction occurs between NO^• and p53 tumor suppressor, in which NO^•-induced DNA damage causes the stabilization and accumulation of p53, which in turn, transrepresses inducible nitric oxide synthase (NOS2) in a negative feedback loop. In chronic inflammatory diseases, for example ulcerative colitis, NO^• induces p53 stabilization and the initiation of DNA-damage response pathway, and also generation of p53 mutation and subsequent clonal selection of p53 mutant cells. Genetic deletion of NOS2 in p53-deficient mice can either suppress or enhance lymphomagenesis depending on the inflammatory microenvironment. These findings highlight the importance of understanding the complex biological interaction of NO^• in the context of the molecular makeup of each individual cancer to design NO^•-targeted treatment strategies.