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.

Graphical abstract

Highlights

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  NO is pro- and anti-tumorigenic. High concentrations of NO maybe anti-tumorigenic.

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  iNOS produces high concentrations of NO and relates to tumor growth or its inhibition.

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  iNOS is associated with cytotoxicity, apoptosis and bystander anti-tumor effects.

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  Tumor- and stromal-iNOS, and the ‘cell situation’ contribute to anti or pro-tumor effects.

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  Dual role of iNOS is influenced by the cell situation and is environment dependent.