NAD+ metabolism, stemness, the immune response, and cancer

Abstract

NAD⁺ was discovered during yeast fermentation, and since its discovery, its important roles in redox metabolism, aging, and longevity, the immune system and DNA repair have been highlighted. A deregulation of the NAD⁺ levels has been associated with metabolic diseases and aging-related diseases, including neurodegeneration, defective immune responses, and cancer. NAD⁺ acts as a cofactor through its interplay with NADH, playing an essential role in many enzymatic reactions of energy metabolism, such as glycolysis, oxidative phosphorylation, fatty acid oxidation, and the TCA cycle. NAD⁺ also plays a role in deacetylation by sirtuins and ADP ribosylation during DNA damage/repair by PARP proteins. Finally, different NAD hydrolase proteins also consume NAD⁺ while converting it into ADP-ribose or its cyclic counterpart. Some of these proteins, such as CD38, seem to be extensively involved in the immune response. Since NAD cannot be taken directly from food, NAD metabolism is essential, and NAMPT is the key enzyme recovering NAD from nicotinamide and generating most of the NAD cellular pools. Because of the complex network of pathways in which NAD⁺ is essential, the important role of NAD⁺ and its key generating enzyme, NAMPT, in cancer is understandable. In the present work, we review the role of NAD⁺ and NAMPT in the ways that they may influence cancer metabolism, the immune system, stemness, aging, and cancer. Finally, we review some ongoing research on therapeutic approaches.

Fig. 1

a Structure of nicotinamide adenine dinucleotide (NAD⁺). This molecule is formed by adenosine monophosphate (AMP) linking to nicotinamide mononucleotide (NMN). AMP is formed by adenosine (in green), ribose ring (in blue) whose hydroxyl (marked in red) can be phosphorylated resulting in NADP+, and phosphate group (in orange). NMN is formed by a ribose ring, phosphate group, and nicotinamide (NAM) (in pink) that is responsible for redox NAD⁺ functions, thus, the atom carbon (marked in red) is capable of accepting a hydride anion (H+, 2e-) leading to the reduced form NADH. In addition to the classical redox functions, NAD⁺ acts as a substrate of multiples enzymes donating the group adenosine diphosphate ribose (ADP-ribose) and releasing nicotinamide as the catabolic reaction product. b Structure of the different states of NAD⁺. NAD⁺ can be phosphorylated to NADP⁺ by NADK enzyme. Thus, NAD⁺ and NADP⁺ can be reduced to NADH or NADPH, respectively. NADH nicotinamide adenine dinucleotide, NAD⁺ nicotinamide adenine dinucleotide, NADP⁺ nicotinamide adenine dinucleotide phosphate, NADPH reduced nicotinamide adenine dinucleotide phosphate

Fig. 2

NAD⁺ in cancer metabolism. Cancer cells rely on glycolysis (pathway in yellow) than mitochondrial oxidative phosphorylation (OXPHOS) (in black) what is called the Warburg Effect. The pentose phosphate pathway (in purple), serine synthesis (in green), and fatty acid synthesis (in blue) are also upregulated in cancer and depend on glycolysis as the core of cancer metabolism. Glutaminolysis (in red) is also upregulated as the main nitrogen source. All these pathways require the cofactor NAD⁺/NADH/NADP+/NADPH as essential cofactors to support faster energy production, counteract ROS production, and synthesis building blocks for tumor proliferation. G6PD glucose-6-phosphate dehydrogenase, GSH glutathione, GSSG glutathione disulfide, ROS reactive oxygen species, GAPDH glyceraldehyde 3-phosphate, LDH lactate dehydrogenase, PRPP 5-phosphoribosyl-1-pyrophosphate

Fig. 3

NAD⁺ biosynthesis pathways. NAD⁺ can be synthesized from the different dietary precursors by de novo pathway (from Trp), the Preiss–Handler pathway (from NA), and the nucleoside pathway (from nicotinic NAR or NR). However, the main source of NAD⁺ is the salvage pathway where the catabolic product (NAM), from NAD⁺-consumed enzymes (sirtuins, PARPs and cADPRSs), is recycled to reconstitute NAD⁺