Nitric Oxide: The Forgotten Child of Tumor Metabolism

Abstract

Nitric oxide (NO) is a signaling molecule with pleiotropic physiological roles in normal cells and pathophysiological roles in cancer. NO synthetase expression and NO synthesis are linked to altered metabolism, neoplasticity, invasiveness, chemoresistance, immune evasion, and ultimately to poor prognosis of cancer patients. Exogenous NO in the microenvironment facilitates paracrine signaling, mediates immune responses, and triggers angiogenesis. NO regulates posttranslational protein modifications, S-nitrosation, and genome-wide epigenetic modifications that can have both tumor-promoting and tumor-suppressing effects. We review mechanisms that link NO to cancer hallmarks, with a perspective of co-targeting NO metabolism with first-line therapies for improved outcome. We highlight the need for quantitative flux analysis to study NO in tumors.

Oxidative stress and antioxidants in the pathophysiology of malignant melanoma

“…NO in TME can be contributed by tumor cells or tumor-associated macrophages (Salimian Rizi et al, 2017). As stated already, melanoma cells expressed both iNOS and nNOS.…”

The Interplay between Antiviral Signalling and Carcinogenesis in Human Papillomavirus Infections

“…A recent study has shown an increase of nitric oxide (NO) and inducible NO synthase (iNOS), which was suggested to be mediated by TLR-induced NF-κB signalling, in cervical samples from HR-HPV-infected patients [133]. Since NO is a critical component of the tumour microenvironment and promotes tumour angiogenesis, as well as tumour cell invasion and metastasis, it has been studied as a possible target for cancer therapy [134].…”

Metabolism within the tumor microenvironment and its implication on cancer progression: An ongoing therapeutic target

“…Thus, the pentose phosphate pathway (PPP) would provide the reducing agent necessary for synthetizing NO. In hypoxic tumors, hypoxia inducible factor 1α (HIF‐1α) interacts with interferon‐gamma (IFN‐γ), thus inducing the expression of inducible NOS (iNOS) . NO produced and secreted by tumor cells reprograms stromal cells to support tumor progression, although high concentrations has been shown to induce apoptosis, and it also helps drug resistance and migration of cancer cells .…”

“…Moreover, NO modulates metabolism of tumor cells, inhibiting prolyl hydroxylase 2 (PHD2) and OXPHOS, hence promoting a glycolytic metabolism . Furthermore, S‐nitrosylation is a mechanism of posttranslational protein modification mediated by NO and implied in modulating the activity of several oncogenic‐signaling cascades and metabolic enzymes …”

“…On the other hand, expression of CD73 in some tumor cells leads to an adenosine accumulation in the extracellular media, which impairs T‐cell function (Figure ) . Additionally, NO production by tumor cells leads to antitumor immunity, whereas its production by myeloid cells promotes this antitumor activity . Since NOS activity requires arginine as a substrate, we dare to ask whether depletion of arginine by tumor cells for the production of NO and polyamines could be the cause to the antitumor immunity (Figure ).…”