Potent Modulation of Intestinal Tumorigenesis in <i>Apcmin/+</i> Mice by the Polyamine Catabolic Enzyme Spermidine/Spermine <i>N</i>1-acetyltransferase
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- Jody M. Tucker
- 1Department of Biological Sciences, University of South Carolina, Columbia, South Carolina;
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- John T. Murphy
- 1Department of Biological Sciences, University of South Carolina, Columbia, South Carolina;
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- Nicholas Kisiel
- 2Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York; and
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- Paula Diegelman
- 2Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York; and
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- Karen W. Barbour
- 1Department of Biological Sciences, University of South Carolina, Columbia, South Carolina;
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- Celestia Davis
- 1Department of Biological Sciences, University of South Carolina, Columbia, South Carolina;
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- Moussumi Medda
- 1Department of Biological Sciences, University of South Carolina, Columbia, South Carolina;
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- Leena Alhonen
- 3A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland
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- Juhani Jänne
- 3A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland
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- Debora L. Kramer
- 2Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York; and
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- Carl W. Porter
- 2Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York; and
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- Franklin G. Berger
- 1Department of Biological Sciences, University of South Carolina, Columbia, South Carolina;
抄録
<jats:title>Abstract</jats:title> <jats:p>Intracellular polyamine pools are homeostatically maintained by processes involving biosynthesis, catabolism, and transport. Although most polyamine-based anticancer strategies target biosynthesis, we recently showed that activation of polyamine catabolism at the level of spermidine/spermine N1-acetyltransferase-1 (SSAT) suppresses tumor outgrowth in a mouse prostate cancer model. Herein, we examined the effects of differential SSAT expression on intestinal tumorigenesis in the ApcMin/+ (MIN) mouse. When MIN mice were crossed with SSAT-overproducing transgenic mice, they developed 3- and 6-fold more adenomas in the small intestine and colon, respectively, than normal MIN mice. Despite accumulation of the SSAT product, N1-acetylspermidine, spermidine and spermine pools were only slightly decreased due to a huge compensatory increase in polyamine biosynthetic enzyme activities that gave rise to enhanced metabolic flux. When MIN mice were crossed with SSAT knock-out mice, they developed 75% fewer adenomas in the small intestine, suggesting that under basal conditions, SSAT contributes significantly to the MIN phenotype. Despite the loss in catabolic capability, tumor spermidine and spermine pools failed to increase significantly due to a compensatory decrease in biosynthetic enzyme activity giving rise to a reduced metabolic flux. Loss of heterozygosity at the Apc locus was observed in tumors from both SSAT-transgenic and -deficient MIN mice, indicating that loss of heterozygosity remained the predominant oncogenic mechanism. Based on these data, we propose a model in which SSAT expression alters flux through the polyamine pathway giving rise to metabolic events that promote tumorigenesis. The finding that deletion of SSAT reduces tumorigenesis suggests that small-molecule inhibition of the enzyme may represent a nontoxic prevention and/or treatment strategy for gastrointestinal cancers.</jats:p>
収録刊行物
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- Cancer Research
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Cancer Research 65 (12), 5390-5398, 2005-06-15
American Association for Cancer Research (AACR)
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詳細情報 詳細情報について
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- CRID
- 1362544418730328704
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- NII論文ID
- 30018589193
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- ISSN
- 15387445
- 00085472
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