Biological Functions and Therapeutic Potential of NAD⁺ Metabolism in Gynecological Cancers

Nicotinamide adenine dinucleotide (NAD⁺) is an important cofactor for both metabolic and signaling pathways, with the dysregulation of NAD⁺ levels acting as a driver for diseases such as neurodegeneration, cancers, and metabolic diseases. NAD⁺ plays an essential role in regulating the growth and progression of cancers by controlling important cellular processes including metabolism, transcription, and translation. NAD⁺ regulates several metabolic pathways such as glycolysis, the citric acid (TCA) cycle, oxidative phosphorylation, and fatty acid oxidation by acting as a cofactor for redox reactions. Additionally, NAD⁺ acts as a cofactor for ADP-ribosyl transferases and sirtuins, as well as regulating cellular ADP-ribosylation and deacetylation levels, respectively. The cleavage of NAD⁺ by CD38-an NAD⁺ hydrolase expressed on immune cells-produces the immunosuppressive metabolite adenosine. As a result, metabolizing and maintaining NAD⁺ levels remain crucial for the function of various cells found in the tumor microenvironment, hence its critical role in tissue homeostasis. The NAD⁺ levels in cells are maintained by a balance between NAD⁺ biosynthesis and consumption, with synthesis being controlled by the Preiss-Handler, de novo, and NAD⁺ salvage pathways. The primary source of NAD⁺ synthesis in a variety of cell types is directed by the expression of the enzymes central to the three biosynthesis pathways. In this review, we describe the role of NAD⁺ metabolism and its synthesizing and consuming enzymes' control of cancer cell growth and immune responses in gynecologic cancers. Additionally, we review the ongoing efforts to therapeutically target the enzymes critical for NAD⁺ homeostasis in gynecologic cancers.