Free radicals are ubiquitous in our body and are generated by normal physiological processes, including aerobic metabolism and inflammatory responses, to eliminate invading pathogenic microorganisms. Chronic inflammation can increase cancer risk. We are investigating the interaction between nitric oxide (NO∙) and p53 as a crucial pathway in inflammatory-mediated carcinogenesis. We have shown previously that the p53 tumor suppressor network is a key responder to microenvironmental components of chronic inflammatory stress including nitric oxide, hydroxyl ions, hypoxia, and DNA replication arrest due to DNA damage by endogenous free radicals. Superoxide fluxes also limit nitric oxidend inactivates it by mutation of p53. Chronic inflammation activates the p53 tumor suppressor network and inactivates it by mutation of p53. Animal models are a critical facet of our integrative biology strategy, hence we have utilized genetic knockouts, e.g., p53 and inducible nitric oxide synthase, to investigate mechanisms of inflammation-associated cancer. Nitric oxide is involved in tumorigenesis. However, the quantity, redox-status, cell type and inflammatory microenvironment determine the pro- and anti-tumorigenic function of nitric oxide. Basal levels of nitric oxide delayed spontaneous tumor development in p53-deficient mice, when compared to mice lacking both p53 and nitric oxide synthase-2. This study provided genetic and mechanistic evidence that nitric oxide can suppress tumorigenesis. However, an inflammation-induced increase in the quantity of nitric oxide accelerated spontaneous tumor development in p53-deficient mice. An inflammatin-induced increase in nitric oxide production inhibited apoptosis and enhanced the production of immune suppressive regulatory T cells. These findings provide evidence that nitric oxide can be tumorigenic. Based on these observations, we propose a model of dose dependent modulation of tumorigenesis by nitric oxide under non-inflammatory and inflammatory microenvironment in a mouse model of cancer-prone Li-Fraumeni syndrome.
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