# Nicotinamide Adenine Dinucleotide (NAD) Metabolism as a Relevant Target in Cancer
## 4 Cancer and NAD+ Metabolism  
Depending on internal genetic or epigenetic changes or microenvironmental conditions, cancer cells can reprogram their metabolism. This metabolic plasticity permits a high growth rate and survival with limited energy resources and adverse conditions. This metabolic plasticity rewiring allows an advantage during tumour progression and survival [26]. Higher ratios of the oxidised forms of NAD+ and NADP+ have been reported in tumour cells than in nontumor cells, suggesting an essential role for NAD+ in this plasticity [27]. Tumour cells are able to switch metabolism from OXPHOS to glycolysis, even under normal oxygen conditions (in a process known as the Warburg effect) [28; 29]. Although OXPHOS metabolism generates energy in a more efficient way, producing 36 ATP molecules, tumour cells prefer glycolysis that generates less energy but in a faster way, producing two ATP molecules. It has been suggested that this fast energy production results in an important competitive advantage in sharing limited nutrients with the microenvironment and stromal cells [30; 31]. However, this is not the only advantage of anaerobic glycolysis; it also allows tumour cells to synthesise macromolecules and counteract ROS production. In fact, part of the pyruvate that is formed is oxidised to acetyl-CoA to enter the Krebs cycle to produce the intermediate compounds of the cycle and use them as biosynthetic precursors. At the same time, these compounds are consumed and must be replenished primarily through the metabolism of glutamine, which is the main source of nitrogen in cells. Tumour cells depend on glutaminolysis for the synthesis of other molecules, such as nonessential amino acids, GSH, NAD+, NADPH and nucleic acids [29; 31; 32; 33]. Some intermediates of glycolysis are also relevant for other processes promoted in cancer cells. For example, the PPP is essential for the synthesis of nucleic acids, DNA replication and the increase in tumour biomass [29; 34]. In addition, the PPP is the main source of NADPH, which is required to reduce the ROS produced by accelerated metabolism, hypoxia or the accumulation of DNA damage in tumour cells. Radio- and chemotherapy also increase  
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.  
ROS levels, and in response, enzymes such as the PI3K/Akt/mTOR pathway, ATM, Ras or Src induce the expression of glucose-6-phosphate dehydrogenase (G6 PDH), activating the PPP [16; 34].  
NAD+-dependent serine synthesis is another glycolysis-dependent pathway that is increased in cancer. The precursor of glycine and cysteine can be serine, which is involved in methionine and folic acid metabolism, redox balance, histone and DNA methylation and amino acid transport in the cells [35; 36]. Metabolism in tumour cells depends highly on the PPP, serine biosynthesis and fatty acid synthesis. These metabolic pathways, which are dependent on NAD+ and NADP+, emerge from glycolysis, making NAD+ biosynthesis a main driver of cancer metabolism [1] (Figure 2).