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An NAD+ dependent/sensitive transcription system: Toward a novel anti-cancer therapy

1 Department of Gene Regulation, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Yamazaki 2641, Noda-shi, Chiba-ken 278-8510, Japan
2 Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Yamazaki 2641, Noda-shi, Chiba-ken 278-8510, Japan
3 Department of Genomic Medical Science, Research Institute of Science and Technology (RIST), Tokyo University of Science, Yamazaki 2641, Noda-shi, Chiba-ken 278-8510, Japan

Cancer is widely known as a “genetic disease” because almost all cancers involve genomic mutations. However, cancer could also be referred to as a metabolic disease because it mainly depends on glycolysis to produce adenosine triphosphate (ATP) and is frequently accompanied by dysfunctions in the mitochondria, which are the primary organelle required in all eukaryotic cells. Importantly, almost all (99%) mitochondrial proteins are encoded by host nuclear genes. Not only cancer but also aging-related diseases, including neurodegenerative diseases, are associated with a decline in mitochondrial functions. Importantly, the nicotinamide adenine dinucleotide (NAD+) level decreases with aging. This molecule not only plays important roles in metabolism but also in the DNA repair system. In this article, we review 5′-upstream regions of mitochondrial function-associated genes to discuss the possibility of whether NAD+ is involved in transcriptional regulations. If the expression of these genes declines with aging, this may cause mitochondrial dysfunction. In this regard, cancer could be referred to as a “transcriptional disease”, and if so, novel therapeutics for cancer will need to be developed.
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Keywords GC box; GGAA motif; mitochondria; nicotinamide adenine dinucleotide (NAD+); TCA cycle; transcription

Citation: Fumiaki Uchiumi, Akira Sato, Masashi Asai, Sei-ichi Tanuma. An NAD+ dependent/sensitive transcription system: Toward a novel anti-cancer therapy. AIMS Molecular Science, 2020, 7(1): 12-28. doi: 10.3934/molsci.2020002


  • 1. Kandoth C, McLellan MD, Vandin F, et al. (2013) Mutational landscape and significance across 12 major cancer types. Nature 502: 333–339.    
  • 2. Rahman N (2014) Realizing the promise of cancer predisposition genes. Nature 505: 302–308.    
  • 3. Aronson S, Rehm H (2015) Building the foundation for genomics in precision medicine. Nature 526: 336–342.    
  • 4. Wishart DS, Mandal R, Stanislaus A, et al. (2016) Cancer metabolomics and the human metabolome database. Metabolomics 6: E10.
  • 5. Warburg O (1956) On the origin of cancer cells. Science 123: 309–314.    
  • 6. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 324: 1029–1033.    
  • 7. Seyfried TN, Flores RE, Poff AM, et al. (2014) Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis 35: 515–527.    
  • 8. Seyfried TN (2015) Cancer as a mitochondrial metabolic disease. Front Cell Develop Biol 3: 43.
  • 9. Vafai SB, Mootha VK (2012) Mitochondrial disorders as windows into an ancient organelle. Nature 491: 374–383.    
  • 10. Zhang J, Pavlova NN, Thompson CB (2017) Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine. EMBO J 36: 1302–1315.    
  • 11. Clunton AA, Lukey MJ, Cerione RA, et al. (2017) Glutamine metabolism in cancer: understanding the heterogeneity. Trends Cancer 3: 169–180.    
  • 12. Martinez-Outschoorn UE, Peiris-Pagés M, Pestell RG, et al. (2017) Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol 14: 11–31.    
  • 13. Spinelli JB, Yoon H, Ringel AE, et al. (2017) Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass. Science 358: 941–946.    
  • 14. Mattaini KR, Sullivan MR, Vander Heiden MG (2016) The importance of serine metabolism in cancer. J Cell Biol 214: 249–257.    
  • 15. Danenberg PV (1977) Thymidylate synthetase-A target enzyme in cancer chemotherapy. Biochim Biophys Acta 473: 73–92.
  • 16. Mathews CK (2015) Deoxyribonucleotide metabolism, mutagenesis and cancer. Nat Rev Cancer 15: 528–539.    
  • 17. Irwin CR, Hitt MM, Evans DH (2017) Targeting nucleotide biosynthesis: a strategy for improving the oncolytic potential of DNA viruses. Front Oncol 7: 229.    
  • 18. Shay JW (2016) Role of telomeres and telomerase in aging and cancer. Cancer Discovery 6: 584–593.    
  • 19. Sahin E, Colla S, Liesa M, et al. (2011) Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470: 359–365.    
  • 20. Houtkooper RH, Mouchiroud L, Ryu D, et al. (2013) Mitochondrial protein imbalance as a conserved longevity mechanism. Nature 497: 451–457.    
  • 21. Vogelstein B, Papadopoulos N, Velculescu VE, et al. (2013) Cancer genome landscapes. Science 339: 1546–1558.    
  • 22. Gasparre G, Porcelli AM, Lenaz G, et al. (2014) Relevance of mitochondrial genetics and metabolism in cancer development, In: Wallace DC and Youle RJ Eds. Mitochondria, Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 235–251.
  • 23. Troulinaki K, Bano D (2012) Mitochondrial deficiency: a double-edged sword for aging and neurodegeneration. Front Genet 3: 244.
  • 24. Bender DA (2014) Micronutrients, In: Introduction to nutrition and metabolism, Boca Raton, NW, CRC Press, Taylor & Francis Group, 343–349.
  • 25. Gholson RK (1966) The pyridine nucleotide cycle. Nature 212: 933–935.    
  • 26. Rechsteiner M, Catanzarite V (1974) The biosynthesis and turnover of nicotinamide adenine dinucleotide in enucleated culture cells. J Cell Physiol 84: 409–422.    
  • 27. Tanuma S, Sato A, Oyama T, et al. (2016) New insights into the roles of NAD+-poly (ADP-ribose) metabolism and poly (ADP-ribose) glycohydrolase. Curr Protein Pep Sci 17: 668–682.    
  • 28. Chen YR (2013) Mitochondrial dysfunction, In: Villamena, FA, Ed., Basis of oxidative stress: chemistry, mechanisms, and disease pathogenesis, Hoboken, NJ: John Wiley & Sons, Inc., 123–135.
  • 29. Wünschiers R (2012) Carbohydrate Metabolism and Citrate Cycle, In: Michal G, Schomburg D, Eds., Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, 2nd ed, Hoboken, NJ: John Wiley & Sons, Inc., 37–58.
  • 30. Wünschiers R (2012) Nucleotides and Nucleosides. In: Michal G, Schomburg D, Eds., Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, 2nd ed, Hoboken, NJ: John Wiley & Sons, Inc., 124–133.
  • 31. Chaudhuri AR, Nussenzweig A (2017) The multifaceted roles of PARP1 in DNA repair and chromatin remodeling. Nat Rev Mol Cell Biol 18: 610–621.    
  • 32. Maruta H, Okita N, Takasawa R, et al. (2007) The Involvement of ATP produced via (ADP-ribose) (n) in the maintenance of DNA replication apparatus during DNA Repair. Biol Pharm Bull 30: 447–450.    
  • 33. Wright RH, Lioutas A, Le Dily F, et al. (2016) ADP-ribose-derived nuclear ATP synthesis by NUDIX5 is required for chromatin remodeling. Science 352: 1221–1225.    
  • 34. German NJ, Haigis MC (2015) Sirtuins and the metabolic hurdles in cancer. Current Biol 25: R569–R583.    
  • 35. O'Callaghan C, Vassilopoulos A (2017) Sirtuins at the crossroads of stemness, aging, and cancer. Aging Cell 16: 1208–1218.    
  • 36. Hsu WW, Wu B, Liu WR (2016) Sirtuins 1 and 2 are universal histone deacetylases. ASC Chem Biol 11: 792–799.
  • 37. Tan B, Young DA, Lu ZH, et al. (2012) Pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), an enzyme essential for NAD+ biosynthesis, in human cancer cells. J Biol Chem 288: 3500–3511.
  • 38. Cambronne XA, Stewart ML, Kim D, et al. (2016) Biosensor reveals multiple sources for mitochondrial NAD+. Science 352: 1474–1477.    
  • 39. Berridge G, Cramer R, Galione A, et al. (2002) Metabolism of the novel Ca2+-mobilizing messenger nicotinic acid-adenine dinucleotide phosphate via a 2'-specific Ca2+-dependent phosphatase. Biochem J 365: 295–301.    
  • 40. Tran MT, Zsengeller ZK, Berg AH, et al. (2016) PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protection. Nature 531: 528–532.    
  • 41. Gujar AD, Le S, Mao DD, et al. (2016) An NAD+-dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma. Proc Natl Acad Sci USA 113: E8247–E8256.    
  • 42. Zhao H, Tang W, Chen X, et al. (2017) The NAMPT/E2F2/SIRT1 axis promotes proliferation and inhibits p53-dependent apoptosis in human melanoma cells. Biochem Biophys Res Commun 493: 77–84.    
  • 43. Mutz CN, Schwentner R, Aryee DNT, et al. (2017) EWS-FLI1 confers exquisite sensitivity to NAMPT inhibition in Ewing sarcoma cells. Oncotarget 8: 24679–24693.
  • 44. Tan B, Dong S, Shepard RL, et al. (2015) Inhibition of nicotinamide phosphoribosyltransferase (NAMPT), an enzyme essential for NAD+ biosynthesis, leads to altered carbohydrate metabolism in cancer cells. J Biol Chem 290: 15812–15824.    
  • 45. Hufton SE, Moerkerk PT, Brandwijk R, et al. (1999) A profile of differentially expressed genes in primary colorectal cancer using suppression subtractive hybridization. FEBS Lett 463: 77–82.    
  • 46. Van Beijnum JR, Moerkerk PT, Gerbers AJ, et al. (2002) Target validation for genomics using peptide-specific phage antibodies: a study of five gene products overexpressed in colorectal cancer. Int J Cancer 101: 118–127.    
  • 47. Bi TQ, Che XM, Liao XH, et al. (2011) Over expression of Nampt in gastric cancer and chemopotentiating effects of the Nampt inhibitor FK866 in combination with fluorouracil. Oncol Rep 26: 1251–1257.
  • 48. Ogino Y, Sato A, Uchiumi F, et al. (2018) Cross resistance to diverse anticancer nicotinamide phosphoribosyltransferase inhibitors induced by FK866 treatment. Oncotarget 9: 16451–16461.
  • 49. Chowdhry S, Zanca C, Rajkumar U, et al. (2019) NAD metabolic dependency in cancer is shaped by gene amplification and enhancer remodelling. Nature 569: 570–575.    
  • 50. Ulanovskaya OA, Zhul AM, Cravatt BF (2013) NNMT promotes epigenetic remodelling in cancer by creating a metabolic methylation sink. Nat Chem Biol 9: 300–306.    
  • 51. Eckert MA, Coscia F, Chryplewicz A, et al. (2019) Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts. Nature 569: 723–728.    
  • 52. Cantó C, Houtkooper RH, Pirinen E, et al. (2012) The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab 15: 838–847.    
  • 53. Han X, Tai H, Wang X, et al. (2016) AMPK activation protects cells from oxidative stress-induced senescence via autophagic flux restoration and intracellular NAD elevation. Aging Cell 15: 416–427.    
  • 54. Yang Y, Sauve AA (2016) NAD+ metabolism: bioenergetics, signaling and manipulation for therapy. Biochim Biophys Acta 1864: 1787–1800.    
  • 55. Zhang H, Ryu D, Wu Y, et al. (2016) NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352: 1436–1443.    
  • 56. Rehmani I, Liu F, Liu A (2013) Cell signaling and transcription, In: Villamena FA, Ed., Molecular basis of oxidative stress: chemistry, mechanisms, and disease pathogenesis, Hoboken, NJ: John Wiley & Sons, 179–201.
  • 57. Yun J, Finkel T (2014) Mitohormesis. Cell Metab 19: 757–766.    
  • 58. López-Otín C, Serrano M, Partridge L, et al. (2013) The hallmarks of aging. Cell 153: 1194–1217.    
  • 59. Santidrian AF, Matsuno-Yagi A, Ritland M, et al. (2013) Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Invest 123: 1068–1081.    
  • 60. Luo C, Lim JH, Lee Y, et al. (2016) PGC1-mediated transcriptional axis suppresses melanoma metastasis. Nature 537: 422–426.    
  • 61. Kamenisch Y, Fousteri M, Knoch J, et al. (2010) Proteins of nucleotide and base excision repair pathways interact in mitochondria to protect from loss of subcutaneous fat, a hallmark of aging. J Exp Med 207: 379–390.    
  • 62. Guarente L (2014) Linking DNA damage, NAD+/SIRT1, and aging. Cell Metab 20: 706–707.    
  • 63. Dang L, White DW, Gross S, et al. (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462: 739–744.    
  • 64. Yan H, Parsons DW, Jin G, et al. (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360: 765–773.    
  • 65. Lu C, Ward PS, Kapoor GS, et al. (2012) IDH mutation impairs histonedemethylation and results in a block to cell differentiation. Nature 483: 474–478.    
  • 66. Uchiumi F, Larsen S, Tanuma S (2013) Transcriptional regulation of the human genes that encode DNA repair- and mitochondrial function-associated proteins, In: Chen, C. Ed., Advances in DNA Repair, Rijeka, Croatia: InTech Open Access Publisher, 129–167.
  • 67. Gray LR, Tompkins SC, Taylor EB (2014) Regulation of pyruvate metabolism and human disease. Cell Mol Life Sci 71: 2577–2604.    
  • 68. Behl C, Ziegler C (2014) Selected age-related disorders, In: Cell Aging: Molecular Mechanisms and Implications for Disease, Heidelberg, Germany: Springer Briefs in Molecular Medicine, Springer Science+Business Media, 99–108.
  • 69. Bender A, Krishnan KJ, Morris CM, et al. (2006) High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 38: 515–517.    
  • 70. Ansari A, Rahman MS, Saha SK, et al. (2017) Function of the SIRT3 mitochondrial deacetylase in cellular physiology, cancer, and neurodegenerative disease. Aging Cell 16: 4–16.    
  • 71. Salvatori I, Valle C, Ferri A, et al. (2018) SIRT3 and mitochondrial metabolism in neurodegenerative diseases. Neurochem Int 109: 184–192.
  • 72. Patel NV, Gordon MN, Connor KE, et al. (2005) Caloric restriction attenuates Abeta-deposition in Alzheimer transgenic models. Neurobiol Aging 26: 995–1000.    
  • 73. Imai S, Guarente L (2010) Ten years of NAD-dependent SIR2 family deacetylases: implications for metabolic diseases. Trends Pharmacol Sci 31: 212–220.    
  • 74. Silva DF, Esteves AR, Oliveira CR, et al. (2017) Mitochondrial metabolism power SIRT2-dependent traffic causing Alzheimer's-disease related pathology. Mol Neurobiol 54: 4021–4040.    
  • 75. Jung ES, Choi H, Song H, et al. (2016) p53-dependent SIRT6 expression protects Ab42-induced DNA damage. Sci Rep 6: 25628.    
  • 76. Blakey CA, Litt MD (2016) Epigenetic gene expression-an introduction, In: Huang S, Litt MD, Blakey CA, Eds, Epigenetic gene expression and regulation, London, UK: Academic Press,Elsevier Inc., 1–19.
  • 77. Suvà ML, Riggi N, Bernstein BE (2013) Epigenetic reprogramming in cancer. Science 339: 1567–1570.    
  • 78. McDevitt MA (2016) Clinical applications of epigenetics. In: M. Fraga, A.F. Fernández, Eds., Epigenomics in health and disease, San Diego, CA: Academic Press, 271–295.
  • 79. Hentze MW, Preiss T (2010) The REM phase of gene regulation. Trends Biochem Sci 35: 423–426.    
  • 80. Gut P, Verdin E (2013) The nexus of chromatin regulation and intermediary metabolism. Nature 502: 489–498.    
  • 81. Liu C, Vyas A, Kassab MA, et al. (2017) The role of poly ADP-ribosylation in the first wave of DNA damage response. Nucleic Acids Res 45: 8129–8141.    
  • 82. Bai P, Cantó C, Oudart H, et al. (2011) PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab 13: 461–468.    
  • 83. Baxter P, Chen Y, Xu Y, et al. (2014) Mitochondrial dysfunction induced by nuclear poly (ADP-ribose) polymerase-1: a treatable cause of cell death in stroke. Transl Stroke Res 5: 136–144.    
  • 84. Uchiumi F, Watanabe T, Ohta R, et al. (2013) PARP1 gene expression is downregulated by knockdown of PARG gene. Oncol Rep 29: 1683–1688.    
  • 85. Gibson BA, Zhang Y, Jiang H, et al. (2016) Chemical genetic discovery of PARP targets reveals a role for PARP-1 in transcription elongation. Science 353: 45–50.    
  • 86. Uchiumi F, Fujikawa M, Miyazaki S, et al. (2013) Implication of bidirectional promoters containing duplicated GGAA motifs of mitochondrial function-associated genes. AIMS Mol Sci 1: 1–26.
  • 87. Desquiret-Dumas V, Gueguen N, Leman G, et al. (2013) Resveratrol induces a mitochondrial complex I dependent increase in NADH oxidation responsible for sirtuin activation in liver cells. J Biol Chem 288: 36662–36675.    
  • 88. Liu J, Oberdoerffer P (2013) Metabolic modulation of chromatin: implications for DNA repair and genomic integrity. Front Genet 4: 182.
  • 89. Pearce EL, Poffenberger MC, Chang CH, et al. (2013) Fueling Immunity: Insights into metabolism and lymphocyte function. Science 342: 1242454.    
  • 90. Uchiumi F, Shoji K, Sasaki Y, et al. (2015) Characterization of the 5'-flanking region of the human TP53 gene and its response to the natural compound, Resveratrol. J Biochem 159: 437–447.
  • 91. Di LJ, Fernandez AG, de Siervi A, et al. (2010) Transcriptional regulation of BRCA1 expression by a metabolic switch. Nat Struct Mol Biol 17: 1406–1413.    
  • 92. Chinnadurai G (2002) CtBP, an unconventional transcription corepressor in development and oncogenesis. Mol Cell 9: 213–224.    
  • 93. Chinnadurai G (2009) The transcription corepressor CtBP: a foe of multiple tumor suppressors. Cancer Res 69: 731–734.    
  • 94. Shen Y, Kapfhamer D, Minnella AM, et al. (2017) Bioenergetic state regulates innate inflammatory responses through the transcriptional co-repressor CtBP. Nat Commun 8: 624.    
  • 95. Chen YQ, Sengchanthalangsy LL, Hackett A, et al. (2000) NF-kappaB p65 (RelA) homodimer uses distinct mechanisms to recognize DNA targets. Structure 8: 419–428.    
  • 96. Yang ZF, Drumea K, Mott S, et al. (2014) GABP transcription factor (nuclear respiratory factor 2) is required for mitochondrial biogenesis. Mol Cell Biol 34: 3194–3201.    
  • 97. Keckesova Z, Donaher JL, De Cock J, et al. (2017) LACTB is a tumor suppressor that modulates lipid metabolism and cell state. Nature 543: 681–686.    
  • 98. Venigopal R, Jaiswal AK (1996) Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P): quinone oxidoreductase1 gene. Proc Natl Acad Sci USA 93: 14960–14965.    
  • 99. Wilson LA, Germin A, Espiritu R, et al. (2005) Ets-1 is transcriptionally up-regulated by H 2 O 2 via an antioxidant response element. FASEB J 19: 2085–2087.    
  • 100. Wei GH, Badis G, Berger MF, et al. (2010) Genome-wide analysis of ETS-family DNA-binding in vitro and in vivo. EMBO J 29: 2147-2160.    
  • 101. Houtkooper RH, Pirinen E, Auwerx J, (2012) Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol 13: 225–238.
  • 102. Sabari BR, Zhang D, Allis CD, et al. (2017) Metabolic regulation of gene expression through histone acylations. Nat Rev Mol Cell Biol 18: 90–101.    
  • 103. Limagne E, Thibaudin M, Euvrard R, et al. (2017) Sirtuin-1 activation controls tumor growth by impeding Th17 differentiation via STAT3 deacetylation. Cell Rep 19: 746–759.    
  • 104. Bonkowski MS, Sinclair DA (2016) Slowing aging by design: the rise of NAD+ and sirtuin-activating compounds. Nat Rev Mol Cell Biol 17: 679–690.    
  • 105. Menzies KJ, Singh K, Saleem A, et al. (2013) Sirtuin 1-mediated effects of exercise and resveratrol on mitochondrial biogenesis. J Biol Chem 288: 6968–6979.    
  • 106. Sack MN, Finkel T (2014) Mitochondrial metabolism, sirtuins, and aging. In: Wallace DC, Youle RJ, Eds, Mitochondria, Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 253–262.
  • 107. Gibson BA, Kraus WL (2012) New insights into the molecular and cellular functions of poly (ADP-ribose) and PARPs. Nat Rev Mol Cell Biol 13: 411–424.    
  • 108. Curtin NJ, Mukhopadhyay A, Drew Y, et al. (2012) The role of PARP in DNA repair and its therapeutic exploitation. In: Kelley MR Ed., DNA repair in cancer therapy-Molecular targets and clinical applications, London, UK: Academic Press, Elsevier Inc., 55–73.
  • 109. Lord CJ, Ashworth A (2017) PARP inhibitors: Synthetic lethality in the clinic. Science 355: 1152–1158.    
  • 110. Venkitaraman AR (2014) Cancer suppression by the chromosome custodians, BRCA1 and BRCA2. Science 343: 1470–1475.    
  • 111. Feng X, Koh DW (2013) Inhibition of poly (ADP-ribose) polymerase-1 or poly (ADP-ribose) glycohydrolase individually, but not in combination, leads to improved chemotherapeutic efficacy in HeLa cells. Int J Oncol 42: 749–756.    
  • 112. Gomes AP, Price NL, Ling AJY, et al. (2013) Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155: 1624–1638.    
  • 113. Mouchiroud L, Houtkooper RH, Auwerx J (2013) NAD+ metabolism, a therapeutic target for age-related metabolic disease. Crit Rev Biochem Mol Biol 48: 397–408.    
  • 114. Williams PA, Harder JM, Foxworth NE, et al. (2017) Vitamin B 3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice. Science 355: 756–760.    
  • 115. Sueishi Y, Nii R, Kakizaki N (2017) Resveratrol analogues like piceatannol are antioxidants as quantitatively demonstrated through the high scavenging ability against reactive oxygen species and methyl radical. Bioorg Med Chem Lett 27: 5203–5206.    
  • 116. Johnson SC, Yanos ME, Kayser EB, et al. (2013) mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science 342: 1524–1528.    
  • 117. Fendt SM, Bell EL, Keibler MA, et al. (2013) Metformin decreases glucose oxidation and increases the dependency of prostate cancer cells on reductive glutamine metabolism. Cancer Res 73: 4429–4438.    
  • 118. Yamato M, Kawano K, Yamanaka Y, et al. (2016) TEMPOL increases NAD+ and improves redox imbalance in obese mice. Redox Biol 8: 316–322.    
  • 119. Jackson SJT, Singletary KW, Murphy LL, et al. (2016) Phytonutrients differentially stimulate NAD(P)H: quinone oxidoreductase, inhibit proliferation, and trigger mitotic catastrophe in Hepa1c1c7 cells. J Med Food 19: 47–53.    
  • 120. Roubalová L, Dinkova-Kostova AT, Biedermann D, et al. (2017) Flavonolignan 2,3-dehydrosilydianin activates Nrf2 and upregulates NAD(P)H: quinone oxidoreductase 1 in Hepa1c1c7 cells. Fitoterapia 119: 115–120.    
  • 121. Son MJ, Ryu JS, Kim JY, et al. (2017) Upregulation of mitochondrial NAD+ levels impairs the clonogenicity of SSEA1+ glioblastoma tumor-initiating cells. Exp Mol Med 49: e344.    
  • 122. Fang EF, Kassahun H, Croteau DL, et al. (2016) NAD+ replenishment improves lifespan and healthspan in ataxia telangiectasia model via mitophagy and DNA repair. Cell Metab 24: 566–581.    
  • 123. Takihara Y, Sudo D, Arakawa J, et al. (2018) Nicotinamide adenine dinucleotide (NAD+) and cell aging, In: Strakoš R and Lorens, B. Ed., New Research on Cell Aging and Death, Hauppauge, NY: Nova Science Publishers, Inc., 131–158.
  • 124. Wartewig T, Kurgyis Z, Keppler S, et al. (2017) PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis. Nature 552: 121–125.    
  • 125. Uchiumi F, Larsen S, Tanuma S (2016) Possible roles of a duplicated GGAA motif as a driver cis-element for cancer-associated genes. In: iConcept, Ed. Understand Cancer – Research and Treatment, Hong Kong: iConcept Press Ltd., 1–25.
  • 126. Uchiumi F, Larsen S, Masumi A, et al. (2013) The putative implications of duplicated GGAA-motifs located in the human interferon regulated genes (ISGs). In: iConcept Ed., Genomics I-Humans, Animals and Plants, Hong Kong: iConcept Press Ltd., 87–105.
  • 127. Uchiumi F, Arakawa J, Iwakoshi K, et al. (2016) Characterization of the 5'-flanking region of the human DNA helicase B (HELB) gene and its response to trans-resveratrol. Sci Rep 6: 24510.    


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