Nicotinamide Adenine Dinucleotide (NAD) Metabolism as a Relevant Target in Cancer

Abstract

NAD+ is an important metabolite in cell homeostasis that acts as an essential cofactor in oxidation-reduction (redox) reactions in various energy production processes, such as the Krebs cycle, fatty acid oxidation, glycolysis and serine biosynthesis. Furthermore, high NAD+ levels are required since they also participate in many other nonredox molecular processes, such as DNA repair, posttranslational modifications, cell signalling, senescence, inflammatory responses and apoptosis. In these nonredox reactions, NAD+ is an ADP-ribose donor for enzymes such as sirtuins (SIRTs), poly-(ADP-ribose) polymerases (PARPs) and cyclic ADP-ribose (cADPRs). Therefore, to meet both redox and nonredox NAD+ demands, tumour cells must maintain high NAD+ levels, enhancing their synthesis mainly through the salvage pathway. NAMPT, the rate-limiting enzyme of this pathway, has been identified as an oncogene in some cancer types. Thus, NAMPT has been proposed as a suitable target for cancer therapy. NAMPT inhibition causes the depletion of NAD+ content in the cell, leading to the inhibition of ATP synthesis. This effect can cause a decrease in tumour cell proliferation and cell death, mainly by apoptosis. Therefore, in recent years, many specific inhibitors of NAMPT have been developed, and some of them are currently in clinical trials. Here we review the NAD metabolism as a cancer therapy target.

Keywords: NAD metabolism; cancer; nicotinamide adenine dinucleotide; therapeutic target.

Figure 1

NAD+ metabolism. Tumour cells depend more on glycolysis (in blue) than on OXPHOS from the mitochondria (in dashed black). The pentose phosphate pathway (in purple), serine biosynthesis (in green), and fatty acid synthesis (in red) are highly activated in cancer and depend on glycolysis, which is the axis of cancer metabolism. Glutaminolysis (in brown) is also increased as the main source of nitrogen in the cell. The NAD+/NADH and NADP+/NADPH cofactors participate in all these pathways, allowing rapid energy production, the elimination of excess ROS, and the synthesis of macromolecules to support tumour proliferation and development.

Figure 2

Different pathways in NAD+ metabolism. De novo pathway, the Preiss–Handler pathway, the salvage pathway and the nucleoside pathway are responsible for maintaining cellular NAD pools to be used in redox and non-redox reactions.

Figure 3

Structure of the NAMPT gene and protein. (A) The NAMPT gene contains 11 exons and 10 introns that are translated into 4 possible variants by alternative splicing or splicing. NAMPT1 is the predominant variant and the only one that has enzymatic activity. The protein contains 2 domains, DUF5593 and NAPRTase, in which the amino acids that form the catalytic site of NAM (D219, G384 and R392) and PRPP (R196, H247 and R311) are located. H247 aa must first be phosphorylated by ATP hydrolysis for NMN synthesis to take place. (B) Crystal structure of the NAMPT functional homodimer (3DHF; https://www.rcsb.org/structure/3DHF, Accessed on 1 April 2022). Catalytic sites are marked with dashed circles.

Figure 4

Brief scheme of CSC contribution to recurrence and metastasis.

Figure 5

Scheme of the proliferation of NAMPT inhibitors in preclinical or clinical stages.