title: Cancer chemoprevention by the antioxidant tempol acts partially via the p53 tumor suppressor.
abstract: We previously demonstrated that the nitroxide antioxidant tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) increased latency to tumorigenesis and doubled (100%) the lifespan of Atm-deficient mice, a mouse model of ataxia telangiectasia, which displays accelerated oxidative damage and stress. Tempol treatment of cancer-prone p53-deficient mice resulted in a small but significant (25%) increase in lifespan by prolonging latency to tumorigenesis, demonstrating that existing oxidative stress and damage are not necessary for the chemopreventative effects of tempol. However, the relatively small effect on latency in p53-deficient mice and the finding that tempol-mediated resistance to oxidative insult was p53-dependent suggested a more direct role of p53 in the chemopreventative effects of tempol. Surprisingly, tempol treatment specifically increased serine 18 phosphorylation of p53 (but not gamma-H2AX) and p21 expression in primary thymocytes in vitro in a p53-dependent fashion. Inhibition of phosphoinositide 3-kinase (PI3K) family members suggested that SMG-1 was responsible for the tempol-mediated enhancement of p53 serine 18 phosphorylation. These data suggest that the chemopreventative effect of tempol is not solely due to the reduction of oxidative stress and damage but may also be related to redox-mediated signaling functions that include p53 pathway activation.
authors.affiliation: Department of Pediatrics, UCSD School of Medicine, La Jolla 92093-0627, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Erker
authors.forename: Ralf
authors.initials: R
authors.lastname: Schubert
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yakushiji
authors.forename: Carrolee
authors.initials: C
authors.lastname: Barlow
authors.forename: Denise
authors.initials: D
authors.lastname: Larson
authors.forename: James B
authors.initials: JB
authors.lastname: Mitchell
authors.forename: Anthony
authors.initials: A
authors.lastname: Wynshaw-Boris
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001260:Ataxia Telangiectasia / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018890:Chemoprevention; D003497:Cyclic N-Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D008136:Longevity / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012694:Serine / Q000737:chemistry / Q000235:genetics; D013113:Spin Labels; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D000975:Antioxidants; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D003497:Cyclic N-Oxides; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D012694:Serine; D013113:Spin Labels; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C493957:Cdkn1a protein, mouse; C576325:Atm protein, mouse; C001803:tempol