Carcinogenesis Advance Access originally published online on August 3, 2007
Carcinogenesis 2007 28(11):2404-2411; doi:10.1093/carcin/bgm162
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Studies of the mechanism by which increased spermidine/spermine N1-acetyltransferase activity increases susceptibility to skin carcinogenesis
Department of Cellular and Molecular Physiology, Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, PO Box 850, Hershey, PA 17033, USA
1 Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48202, USA
2 Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USA
* To whom correspondence should be addressed. Tel: +1 717 531 8152; Fax: +1 717 531 5157;Email: aep1{at}psu.edu
Previous studies have shown that keratin 6 (K6)–spermidine/spermine N1-acetyltransferase (SSAT) transgenic mice, which modestly over-express SSAT in the skin, are more sensitive to tumor induction by a two-stage tumorigenesis protocol using initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). To evaluate the role of altered levels of polyamines and oxidative stress in this increase, studies were carried out with pharmacologic and genetic manipulation of K6–SSAT mice subjected to DMBA/TPA carcinogenesis. The increased tumor incidence was partially prevented by treatment with 1,4-bis-[N-(buta-2,3-dienyl)amino]butane, an inhibitor of acetylpolyamine oxidase which prevented degradation of the acetylated polyamines. This result suggests that toxic products such as reactive oxygen species and aldehydes liberated by the action of polyamine oxidase on the acetylated polyamines formed by SSAT may enhance tumor development. Breeding of the K6–SSAT mice with K6–antizyme (AZ) mice [which express AZ, a negative regulator of ornithine decarboxylase (ODC)] blocked the development of tumors. In addition, treatment of tumor-bearing K6–SSAT mice with the ODC inhibitor, 
-difluoromethylornithine, resulted in the complete regression of established tumors. In contrast, treatment with N1,N11-bis(ethyl)norspermidine which increased SSAT activity in the tumors did not enhance regression. These results indicate that the tumor progression in K6–SSAT mice is dependent on elevated ODC activity and increased putrescine levels and may be further enhanced by oxidative stress. They support the use of strategies to modulate polyamine levels through the inhibition of ODC activity or polyamine uptake, but not via increased SSAT expression, for cancer chemoprevention in individuals at high risk for skin tumor development.
Abbreviations: APAO, acetylpolyamine oxidase; AZ, antizyme; BE-3-3-3, N1,N11-bis(ethyl)norspermidine; DFMO, -difluoromethylornithine; DMBA, 7,12-dimethylbenz[a]anthracene; K6, keratin 6; MDL72527, 1,4-bis-[N-(buta-2,3-dienyl)amino]butane; ODC, ornithine decarboxylase; PCR, polymerase chain reaction; PPAR-
, peroxisome-proliferator-activated receptor ; ROS, reactive oxygen species; SSAT, spermidine/spermine N1-acetyltransferase; TPA, 12-O-tetradecanoylphorbol-13-acetate
These authors contributed equally to this work. Received February 26, 2007; revised July 11, 2007; accepted July 12, 2007.
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