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.
Highlights
Nitric oxide (NO) is a biologically unstable, lipophilic, extremely diffusible, free radical that regulates numerous biological functions [1]
The involvement of cyclic guanosine monophosphate (cGMP) in growth inhibition has been identified in vascular smooth muscle cells (VSMCs), in which guanylate cyclase (GC) interacts with NO produced by eNOS with a subsequent increase in cGMP and repression of the epidermal growth factor signalling pathway [30,31]
S-nitrosation of adenine DNA glycosylase (AAG) has been found to increase the activity of AAG [111]. This coupled with the impact of NO on APE export to the cytoplasm may lead to base excision repair (BER) enzymatic machinery imbalance, disrupting the effectiveness of BER in NO related DNA Damage Repair (DDR).mismatch repair (MMR) fixes replication associated errors that can arise due to insertion, deletion, and mis-incorporation of bases in the newly synthesised strand during DNA replication (Figure 2c) [112]
Summary
Nitric oxide (NO) is a biologically unstable, lipophilic, extremely diffusible, free radical that regulates numerous biological functions [1]. NO reacts with superoxide (O2−) to yield peroxynitrite (ONOO−) (Equation (2)) This species has varied reactivity, but a major biological pathway involves rapid interaction with carbon dioxide to form nitrosoperoxycarbonate (ONOOCO2-). While this reactive species leads mostly to nitrate (Equation (3)) [10], it can generate the carbonate and NO2 radicals (Equation (4)), which can react with a wide range of biomolecules including nucleic acids, amino acids, lipids, metal containing proteins [11]. The imbalance between the production and consumption rates of free radicals including reactive oxygen species (ROS) and reactive nitrogen species (RNS) can cause oxidative and nitrosative stress [16]. Here, we review the various actions of NO and its by-products in cancer and discuss how they may be leveraged as a novel therapeutic strategy in personalised cancer treatment
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