Abstract
Studies presented here show that cellular NAD, which we hypothesize to be the relevant biomarker of niacin status, is significantly lower in humans than in the commonly studied animal models of carcinogenesis. We show that nicotinamide and the resulting cellular NAD concentration modulate expression of the tumor suppressor protein, p53, in human breast, skin, and lung cells. Studies to determine the optimal NAD concentrations for responding to DNA damage in breast epithelial cells reveal that DNA damage appears to stimulate NAD biosynthesis and that recovery from DNA damage occurs several hours earlier in the presence of higher NAD or in cells undergoing active NAD biosynthesis. Finally, analyses of normal human skin tissue from individuals diagnosed with actinic kératoses 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 strategies in carcinogenesis.
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References
Jacobson EL, Smith JY, Wielckens K, Hilz H, Jacobson MK: Cellular recovery of dividing and confluent C3H10T1/2 cells from N-methyl-N-nitro-N-nitrosoguanidine in the presence of ADP-ribosylation inhibitors. Carcinogenesis 6: 715–718, 1985
Shah GM, Shah RG, Poirier GG: Different cleavage pattern for poly(ADP-ribose) polymerase during necrosis and apoptosis in HL-60 cells. Biochem Biophys Res Commun 229: 838–844, 1996
Vu CQ, Coyle DL, Tai H-H, Jacobson EL, Jacobson MK: Intramolecular ADP-ribose transfer reactions and calcium signalling. In: F. Haag, F. Koch-Nolte (eds). ADP-Ribosylation in Animal Tissues: Structure, Function, and Biology of Mono-ADP-Ribosyltransferases and Related Enzymes. Plenum Press, New York, 1997, pp 381–388
Vu CQ, Coyle DL, Jacobson EL, Jacobson MK: Intracellular signaling by cyclic ADP-ribose in oxidative cell death. FASEB J 11:Al 116, 1997
Wright SC, Wei QS, Kinder DH, Larrick JW: Biochemical pathways of apoptosis: nicotinamide adenine dinucleotide-deficient cells are resistant to tumor necrosis factor or ultraviolet light activation of the 24-kD apoptotic protease and DNA fragmentation. J Exp Med 183: 463–471, 1996
Whitacre CM, Hashimoto H, Hashimoto S, Tsai M-L, Chatterjee S, Berger SJ, Berger NA: Involvement of NAD-poly(ADP-ribose) metabolism in p53 regulation and its consequences. Cancer Res 55: 3697–3701, 1995
Nutrition monitoring in the United States: A progress report from the joint nutrition monitoring evaluation committee. Vol DHHS Publication No.(PHS)86-1255, 1986
Fu CS, Swendseid ME, Jacob RA, McKee RW: Biochemical markers for assessment of niacin status in young men: Levels of erythrocyte niacin coenzymes and plasma tryptophan. J Nutr 119: 1949–1955, 1989
Jacobson EL, Dame A, Pyrek JS, Jacobson MK: Evaluating the role of niacin in human carcinogenesis. Biochimie 77: 394–398, 1995
Jacobson EL, Huang AC, Williams T, Gensler HL: Chemoprevention by niacin in a mouse model of UV-induced skin carcinogenesis. Proc Am Assoc Cancer Res 37: A279, 1996
Zhang JZ, Henning SM, Swendseid ME: Poly (ADP-ribose) polymerase activity and DNA strand breaks are affected in tissues of niacin deficient rats. J Nutr 123: 1349–1355, 1993
Rawling JM, Jackson TM, Driscoll E, Kirkland JB: Dietary niacin deficiency lowers tissue poly(ADP-ribose) and NAD+ concentrations in Fischer-344 rats. J Nutr 124: 1597–1603, 1994
Shibata K, Murata K: Blood NAD as an index of niacin nutrition. Nutr Inter 2: 177–181, 1986
Jacobson EL, Jacobson MK: Tissue NAD as a biochemical measure of niacin status in humans. Meth Enzymol 280: 221–230, 1997
Jacobson EL, Jacobson MK: A biomarker for the assessment of niacin nutriture as a potential preventive factor in carcinogenesis. J Int Med 233: 59–62, 1993
Jacobson EL: Niacin deficiency and cancer in women. J Am Coll Nutr 12: 412–416, 1993
Kirkland JB, Rawling JM: Niacin. In: R. Rucker, J. Suttie, D. McCormick, L. Machlin (eds). Handbook of Vitamins, 3rd ed. Marcel Dekker, New York, 1998 (in press)
Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA Jr, Butel JS, Bradley A: Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumors. Nature 356: 215–221, 1992
Bradford MM: A rapid and sensitive method for the quantitation of microgram, quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248–254, 1976
Hammond SL, Ham RG, Stampfer MR: Serum-free growth of human mammary epithelial cells: Rapid clonal growth in defined medium and extended serial passage with pituitary extract. Proc Nati Acad Sci 81: 5435–5439, 1984
McKeehan WL, McKeehan KA, Hammond SL, Ham RG: Improved medium for clonal growth of human diploid fibroblasts at low concentrations of serum protein. In Vitro 13: 399–416, 1977
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© 1999 Springer Science+Business Media New York
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Jacobson, E.L., Shieh, W.M., Huang, A.C. (1999). Mapping the role of NAD metabolism in prevention and treatment of carcinogenesis. In: Alvarez-Gonzalez, R. (eds) ADP-Ribosylation Reactions: From Bacterial Pathogenesis to Cancer. Molecular and Cellular Biochemistry: An International Journal for Chemical Biology in Health and Disease, vol 30. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-8740-2_10
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DOI: https://doi.org/10.1007/978-1-4419-8740-2_10
Publisher Name: Springer, Boston, MA
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