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Human Molecular Genetics Advance Access published online on May 11, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi181
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>© The Author 2005. Published by Oxford University Press. All rights reserved
Received March 18, 2005
Revised May 1, 2005
Accepted May 1, 2005

Article

Cancer chemoprevention by the antioxidant tempol acts partially via the p53 tumor suppressor

Laura Erker 1, Ralf Schubert 1, Hiroyuki Yakushiji 1, Carrolee Barlow 2, Denise Larson 2, James B. Mitchell 3, and Anthony Wynshaw-Boris 4*

1 Departments of Pediatrics, Medicine and the Comprehensive Cancer Center, UCSD School of Medicine, La Jolla 92093 U.S.A
2 Genetic Disease Research Branch, NHGRI, NIH, Bethesda, MD 20892 U.S.A
3 Radiation Biology Branch, NCI, Bethesda, MD 20892 U.S.A
4 Departments of Pediatrics, Medicine and the Comprehensive Cancer Center, UCSD School of Medicine, La Jolla 92093 U.S.A; Genetic Disease Research Branch, NHGRI, NIH, Bethesda, MD 20892 U.S.A

* To whom correspondence should be addressed.
Anthony Wynshaw-Boris, E-mail: awynshawboris{at}ucsd.edu


  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 (AT) that displays accelerated oxidative damage and stress (Schubert et al. Human Mol. Genet. 33:425, 2004). Tempol treatment of cancer-prone p53-deficient mice resulted in a smaller 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. This data suggests 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.


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