The dual role of iNOS in cancer

Abstract

Nitric oxide (NO) is one of the 10 smallest molecules found in nature. It is a simple gaseous free radical whose predominant functions is that of a messenger through cGMP. In mammals, NO is synthesized by the enzyme nitric oxide synthase (NOS) of which there are three isoforms. Neuronal (nNOS, NOS1) and endothelial (eNOS, NOS3) are constitutive calcium-dependent forms of the enzyme that regulate neural and vascular function respectively. The third isoform (iNOS, NOS2), is calcium-independent and is inducible. In many tumors, iNOS expression is high, however, the role of iNOS during tumor development is very complex and quite perplexing, with both promoting and inhibiting actions having been described. This review will aim to summarize the dual actions of iNOS-derived NO showing that the microenvironment of the tumor is a contributing factor to these observations and ultimately to cellular outcomes.

Keywords: Apoptosis; Cancer; Cell situation; Nitric oxide; Stroma; iNOS.

Graphical abstract

Fig. 1

Biosynthesis of NO and its mechanism of action. NO is produced by three nitric oxide synthase (NOS) isoforms neuronal, endothelial, and inducible (nNOS, eNOS, and iNOS) that catalyze the oxidation of l-arginine to l-citrulline. NO activates the enzyme sGC to increase cGMP production that has downstream signaling effects. NO also has biological action by modification of protein through S-nitrosylation.

Fig. 2

NO modulates various cellular activities by altering multiple pathways. Abbrv: PI3K-AKT: Phosphatidylinositol-3-Kinase and Protein Kinase B; MAPK: Mitogen-activated protein kinase; ERK: Extracellular signal-regulated kinase; JNK: c-Jun N-terminal protein kinase; VEGF: Vascular endothelial growth factor; HIF: Hypoxia inducible factor; COX2: Cytochrome Oxidase subunit 2; IL8: Interleukin 8; PGE2: Prostaglandin E2; Cyt c: Cytochrome c; Bcl-2: B-cell lymphoma 2; HSP70: Heat Shock protein 70; RKIP: Raf kinase inhibitor protein; EMT: Epithelial Mesenchymal transition; Bcl-xl: B-cell lymphoma-extra large XIAP: X-linked inhibitor of apoptosis protein; MMP: Matrixmetalloproteinase; cGMP: Cyclic guanosine monophosphate; NO: nitric oxide.

Fig. 3

The transcription factor NF-κB is central to iNOS regulation. LPS, IL-1β, TNF-α, and IL-6 have been shown to induce iNOS, whereas glucocorticoids (GlC), transforming growth factor-β1 (TGFβ1), antioxidants (e.g. pyrrolidine dithiocarbamate, PDTC) and inhibitors of phosphatidylcholine-specific phospholipase (PC-PLC) have been shown to inhibit iNOS expression by inhibiting NF-κB activation.