NAD-Biosynthetic and Consuming Enzymes as Central Players of Metabolic Regulation of Innate and Adaptive Immune Responses in Cancer

Abstract

Cancer cells, particularly in solid tumors, are surrounded by non-neoplastic elements, including endothelial and stromal cells, as well as cells of immune origin, which can support tumor growth by providing the right conditions. On the other hand, local hypoxia, and lack of nutrients induce tumor cells to reprogram their metabolism in order to survive, proliferate, and disseminate: the same conditions are also responsible for building a tumor-suppressive microenvironment. In addition to tumor cells, it is now well-recognized that metabolic rewiring occurs in all cellular components of the tumor microenvironment, affecting epigenetic regulation of gene expression and influencing differentiation/proliferation decisions of these cells. Nicotinamide adenine dinucleotide (NAD) is an essential co-factor for energy transduction in metabolic processes. It is also a key component of signaling pathways, through the regulation of NAD-consuming enzymes, including sirtuins and PARPs, which can affect DNA plasticity and accessibility. In addition, both NAD-biosynthetic and NAD-consuming enzymes can be present in the extracellular environment, adding a new layer of complexity to the system. In this review we will discuss the role of the “NADome” in the metabolic cross-talk between cancer and infiltrating immune cells, contributing to cancer growth and immune evasion, with an eye to therapeutic implications.

Quinolinate as a Marker for Kynurenine Metabolite Formation and the Unresolved Question of NAD+ Synthesis During Inflammation and Infection

“…It is possible that prolonged dietary tryptophan excess during a strong immune response may turn out to be an exacerbating factor in certain inflammatory conditions, shifting kynurenine pathway flux from a net positive to an overall negative effect. The effects of excessive kynurenine flux on cancer cell evasion may be another pathology associated with excess tryptophan in the diet (121).…”

NAMPT and NAPRT: Two Metabolic Enzymes With Key Roles in Inflammation

“…Through their functional activities of post-translational modifications (ADP-ribosylation and deacetylation), or through the modulation of Ca 2+ signaling, these enzymes regulate gene transcription, cell differentiation, cell cycle progression, circadian rhythm, DNA repair, chromatin stability, cell adaptation to stress signals, and immune responses (41,42). Therefore, PARPs and sirtuins represent connecting elements between the metabolic state of a cell and its signaling and transcriptional activities (43).…”

“…Total intracellular levels are maintained between 200 and 500 µM, depending on the cell type or tissue, increasing in response to different stimuli (43). NAD homeostasis is the result of the balance between a number of NAD-consuming reactions and NAD-biosynthetic routes, via three distinct pathways: the de novo biosynthetic pathway, the Preiss-Handler pathway, and the salvage pathway, as reviewed in Houtkooper et al (27), Ruggieri et al 29, and Audrito et al (42) and illustrated in Figure 2.…”

“…The distal promoter region contains several CAAT boxes and TATA-like sequences, as well as binding sites for nuclear factor 1 (NF-1), nuclear factor kappa-lightchain-enhancer of activated B cells (NF-κB), CCAAT/enhancer binding protein (C/EBPβ), the glucocorticoid receptor (GR), and activating protein 1 (AP-1) (101). The majority of these transcription factors, including NF-1, AP-1, AP-2, NF-κB, and STAT, regulate cytokine expression and their presence in the promoter region of NAMPT suggests a role for this enzyme in immunity (42,105).…”

NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview

“…Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of NAD salvage pathway, is the greatest contributor in generating NAD in mammals [1,2]. Overexpression of NAMPT has been implicated in several cancers [3][4][5]. On the other hand, nicotinate phosphoribosyltransferase (NAPRT) also produces NAD through the nicotinic acid pathway [1,6].…”