Nitric Oxide: The Forgotten Child of Tumor Metabolism

NO is a key messenger in the TME with pro- and antitumorigenic roles. NO is emerging as a key regulator of cancer metabolism via S-nitrosation of enzymes. NO has a wide range of control over gene expression in tumors via NO-mediated epigenetic modifications Quantified approach to studying effects of NO synthesis in cancers should guide the design of therapies targeting NO – from in vitro experiments to clinical trials. 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. 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. the process of formation of new blood vessels that branch out of existing blood vessels. This process is essential for wound healing in normal tissue, however, it is also essential for malignant tumor growth. a subpopulation of cells within the tumor that are transformed fibroblasts, but share properties of myofibroblasts that are found during the process of wound healing. a novel concept where genes or metabolic enzymes that are involved in a strong interplay to promote disease progression are both targeted to achieve a synergistic therapeutic effect. it is the subset of cellular metabolic function responsible for the generation of energy currency molecule, ATP, by breaking down nutrients. environmental factors can lead to modifications in the DNA strands or histones around which DNA strands are wrapped, which can regulate transcription. These are in the form of reversible attachment of methyl and/or acetyl groups on segments of the DNA or on histone tails. a computational technique that uses mass balance principles to estimate intracellular metabolic rates (or fluxes) from empirically measurable metabolic parameters. Fluxes are the closest representation of metabolic pathway activity. the process of protein post-translational modification, where NO is attached to the thiol group of a cysteine residue. It can cause repression or enhance protein activity depending on the protein and location of the active thiol group. the range of drug dose that targets cancer cells effectively but avoids adversely affecting healthy cells to minimize side effects. these protein receptors are characterized by their ability to respond to invading pathogens by recognizing conserved molecular structures. TLRs are primarily expressed by immune cells such as monocytes, macrophages, mast cells, and dendritic cells. Upregulated TLR expression has been found in almost all types of cancer cells and has been linked to oncogenesis and cancer progression. TLR agonists are emerging as antitumor agents and are exploited to enhance the immunogenicity of current chemotherapeutic regimens. tumors are populations of cancer cells and non-neoplastic stroma cells including fibroblasts, vascular cells, immune cells, bone marrow-derived inflammatory cells, lymphocytes, and the extracellular matrix (ECM). The vicinity in which malignant cells thrive by dynamically interacting with the nonmalignant components is known as the TME.