Mapping the role of NAD metabolism in prevention and treatment of carcinogenesis

Studies presented here show that cellular NAD, which we hypothesize to be t he relevant biomarker of niacin status, is significantly lower in humans th an in the commonly studied animal models of carcinogenesis. We show that ni cotinamide and the resulting cellular NAD concentration modulate expression of the tumor suppressor protein, p53, in human breast, skin, and lung cell s. Studies to determine the optimal NAD concentrations for responding to DN A damage in breast epithelial cells reveal that DNA damage appears to stimu late NAD biosynthesis and that recovery from DNA damage occurs several hour s earlier in the presence of higher NAD or in cells undergoing active NAD b iosynthesis. Finally, analyses of normal human skin tissue from individuals diagnosed with actinic keratoses or squamous cell carcinomas show that NAD content of the skin is inversely correlated with the malignant phenotype. Since NAD is important in modulating ADP-ribose polymer metabolism, cyclic ADP-ribose synthesis. and stress response proteins, such as p53, following DNA damage, understanding how NAD metabolism is regulated in the human has important implications in developing both prevention and treatment strategi es in carcinogenesis.