Nitric oxide in gastrointestinal epithelial cell carcinogenesis: linking inflammation to oncogenesis

Abstract

Chronic inflammation of gastrointestinal tissues is a well-recognized risk factor for the development of epithelial cell-derived malignancies. Although the inflammatory mediators linking chronic inflammation to carcinogenesis are numerous, current information suggests that nitric oxide (NO) contributes to carcinogenesis during chronic inflammation. Inducible nitric oxide synthase (iNOS), expressed by both macrophages and epithelial cells during inflammation, generates the bioreactive molecule NO. In addition to causing DNA lesions, NO can directly interact with proteins by nitrosylation and nitosation reactions. The consequences of protein damage by NO appear to be procarcinogenic. For example, NO inhibits DNA repair enzymes such as human 8-oxodeoxyguanosine DNA glycosylase 1 and blocks apoptosis via nitrosylation of caspases. These cellular events permit DNA damage to accumulate, which is required for the numerous mutations necessary for development of invasive cancer. NO also promotes cancer progression by functioning as an angiogenesis factor. Strategies to inhibit NO generation during chronic inflammation or to scavenge reactive nitrogen species may prove useful in decreasing the risk of cancer development in chronic inflammatory gastrointestinal diseases.

As(III) inhibits ultraviolet radiation-induced cyclobutane pyrimidine dimer repair via generation of nitric oxide in human keratinocytes

“…For example, an NO donor caused irreversible damage to the zinc finger-containing DNA repair enzyme formamidopyrimidine -DNA glycolyase (46) and the poly (ADP-ribose) polymerase (PARP) family of nuclear enzymes, which play an important role in maintaining genome stability, are also inhibited by NO (47). In view of the fact that environmentally relevant concentration of 0.5 μM is sufficient to interfere with CPD repair, it seems quite feasible that generation of NO by As(III) represents a potential underlying mechanism for the observed inhibition of DNA repair processes (46)(47)(48).…”

NF-κB signaling, liver disease and hepatoprotective agents

“…Chronic H. pylori infection also results in the release of mutagenic substances such as iNOS metabolites which can induce oncogenic mutations (Mannick et al, 1996). NO generated by iNOS is converted to reactive nitrogen species, which can exert oncogenic effects including direct DNA damage, oncogenic mutations, inhibition of apoptosis and may also promote angiogenesis (Jaiswal et al, 2001). H. pylori infection is also known to induce the expression of the proinflammatory cyclooxygenase 2 (COX-2) enzyme (Salvemini et al, 1993;Ristimaki et al, 1997;Sung et al, 2000).…”

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

“…Notably, TAMs have also been found to actively associate with tumor cells via adhesion molecules, such as ICAM-1 and sialoadhesin, and to convey them into efferent blood vessels [220]. Since macrophage activity is associated with the release of reactive oxygen and other mutagenic compounds, they might also indirectly induce additional genetic pro-tumorigenic and pro-metastatic alterations [3,4,221].…”