The Role of Nitric Oxide in Cancer: Master Regulator or NOt?

Abstract

Nitric oxide (NO) is a key player in both the development and suppression of tumourigenesis depending on the source and concentration of NO. In this review, we discuss the mechanisms by which NO induces DNA damage, influences the DNA damage repair response, and subsequently modulates cell cycle arrest. In some circumstances, NO induces cell cycle arrest and apoptosis protecting against tumourigenesis. NO in other scenarios can cause a delay in cell cycle progression, allowing for aberrant DNA repair that promotes the accumulation of mutations and tumour heterogeneity. Within the tumour microenvironment, low to moderate levels of NO derived from tumour and endothelial cells can activate angiogenesis and epithelial-to-mesenchymal transition, promoting an aggressive phenotype. In contrast, high levels of NO derived from inducible nitric oxide synthase (iNOS) expressing M1 and Th1 polarised macrophages and lymphocytes may exert an anti-tumour effect protecting against cancer. It is important to note that the existing evidence on immunomodulation is mainly based on murine iNOS studies which produce higher fluxes of NO than human iNOS. Finally, we discuss different strategies to target NO related pathways therapeutically. Collectively, we present a picture of NO as a master regulator of cancer development and progression.

Plasma Treated Water Solutions in Cancer Treatments: The Contrasting Role of RNS

“…Within the tumor microenvironment, low to moderate levels of ● NO derived from cancer and endothelial cells can activate angiogenesis and epithelial-to-mesenchymal transition, promoting an aggressive phenotype [ 68 ]. For this reason, to assess what happens when cancer and hybrid ECs are exposed to NOx species, excluding ● NO, in combination with ROS (i.e., H 2 O 2 ) is fundamental for further application of such liquids in cancer therapy and in general to gain new insights in tumor progression.…”

Dynamic alteration in miRNA and mRNA expression profiles at different stages of chronic arsenic exposure-induced carcinogenesis in a human cell culture model of skin cancer

“…Data at 28-wk time point also reveal dysregulation of several critical pathways classically associated with a wide variety of cancers. e-NOS signaling, a master regulator of cancer development (Khan et al 2020) including skin cancer (Bruch-Gerharz et al 1998;Dhar et al 2002), is inhibited (Fig. 3B and Supplementary Table 5).…”

Hypericum Perforatum Extract Modifies Serum and Tumoral Redox Status and Nitric Oxide Metabolites in Mice

“…The dichotomic pro-or antitumoral features of NO depend on cellular status and redox state, local concentrations and duration of exposure, and compartmentalization of NO production (González et al 2018). In circumstances, when its levels reach to very high concentrations, NO could arrest the cell cycle and induce apoptosis protecting against initiation and progression of cancer such as after robust release from iNOS-expressing Th1 lymphocytes and M1-polarised macrophages under highly-activated conditions (Khan et al 2020). But as suggested above, the actions of NO on cancer biology is biphasic and it can be proposed that the inherent nature of tumor-driven NO dominantly propagates cancer growth.…”

“…During initiation of carcinogenesis, NO can delay cell cycle progression, allowing for erratic DNA repair that stimulates the accumulation of mutations and causing tumor heterogeneity (Khan et al 2020). During progression of cancer, low to moderate (even supraphysiological) levels of NO origined from malignant and endothelial cells can induce angiogenesis, epithelial-to-mesenchymal transition and an aggressive biology (Khan et al 2020). A well-delineated feature by which NO modifies cell functions is the posttranslational modification of cysteine thiols in target proteins by a biochemical phenomenon defined as Snitrosylation (Iyer et al 2014).…”