Briefing on Nitric Oxide a Signal Molecule in Cancer Metastasis and Therapeutic Target

Nitric oxide (NO) is an important signaling molecule in maintaining normal physiological processes like blood flow, neurotransmission and immune regulation. In cancer, it exhibits a dual role in context-dependent mechanism. At low levels, it activates angiogenesis, migration and tumor promotion; on the other hand, with an increase in concentration, it promotes apoptosis and has an anti-metastatic effect. Hence, regulated levels of NO are required to maintain normal hemostasis. NO has temporal and spatial regulation as its pro- and anti-metastatic effects are decided by the tumor stage, tumor microenvironment, and nitric oxide synthase isoforms expression. NO regulates EMT markers like upregulation of Snail, Twist, and ZEB1 (pro-EMT factors and downregulation of E-cadherin. NO also regulates the crosstalk between signaling factors, such as TGF-β, Wnt/β-catenin and NF-κB; during EMT and hypoxia-induced angiogenesis. NO promotes immunosuppression and metastasis by interacting with tumor-associated macrophages and myeloid-derived suppressor cells, which express iNOS. NO activates cancer promotion pathways like NF-κB, upregulates pro-metastatic genes (MMPs, cytokines), PI3K/Akt/mTOR and p53/Nrf2, along with regulating non-coding RNAs. Thus, NO is a potential target in cancer therapeutics and reviews focus on the new advancements using NO as a potential biomarker and therapeutic agent.