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J. Biol. Chem., Vol. 279, Issue 38, 40076-40083, September 17, 2004

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Activated Polyamine Catabolism Depletes Acetyl-CoA Pools and Suppresses Prostate Tumor Growth in TRAMP Mice^*

Kristin Kee, Barbara A. Foster, Salim Merali, Debora L. Kramer, Mary L. Hensen, Paula Diegelman, Nicholas Kisiel, Slavoljub Vujcic, Richard V. Mazurchuk¶, and Carl W. Porter||

From the Departments of Pharmacology and Therapeutics and ^¶Cancer Biology, Roswell Park Cancer Institute, Buffalo, New York 14263 and the Department of Medical and Molecular Parasitology, New York University School of Medicine, New York, New York 10010

The enzyme spermidine/spermine N¹-acetyltransferase (SSAT) regulates the catabolism and export of intracellular polyamines. We have previously shown that activation of polyamine catabolism by conditional overexpression of SSAT has antiproliferative consequences in LNCaP prostate carcinoma cells. Growth inhibition was causally linked to high metabolic flux arising from a compensatory increase in polyamine biosynthesis. Here we examined the in vivo consequences of SSAT overexpression in a mouse model genetically predisposed to develop prostate cancer. TRAMP (transgenic adenocarcinoma of mouse prostate) female C57BL/6 mice carrying the SV40 early genes (T/t antigens) under an androgen-driven probasin promoter were cross-bred with male C57BL/6 transgenic mice that systemically overexpress SSAT. At 30 weeks of age, the average genitourinary tract weights of TRAMP mice were 4 times greater than those of TRAMP/SSAT bigenic mice, and by 36 weeks, they were 12 times greater indicating sustained suppression of tumor outgrowth. Tumor progression was also affected as indicated by a reduction in the prostate histopathological scores. By immunohistochemistry, SV40 large T antigen expression in the prostate epithelium was the same in TRAMP and TRAMP/SSAT mice. Consistent with the 18-fold increase in SSAT activity in the TRAMP/SSAT bigenic mice, prostatic N¹-acetylspermidine and putrescine pools were remarkably increased relative to TRAMP mice, while spermidine and spermine pools were minimally decreased due to a compensatory 5-7-fold increase in biosynthetic enzymes activities. The latter led to heightened metabolic flux through the polyamine pathway and an associated 70% reduction in the SSAT cofactor acetyl-CoA and a 40% reduction in the polyamine aminopropyl donor S-adenosylmethionine in TRAMP/SSAT compared with TRAMP prostatic tissue. In addition to elucidating the antiproliferative and metabolic consequences of SSAT overexpression in a prostate cancer model, these findings provide genetic support for the discovery and development of specific small molecule inducers of SSAT as a novel therapeutic strategy targeting prostate cancer.

Received for publication, May 28, 2004

^* This work was supported in part by National Institutes of Health Grant CA-76428 and by Department of Defense Grant DAMD17-03-1-0024, Core Grant CA16056, and Predoctoral Training Grant CA10972. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence and requests for reprints should be addressed: Dept. of Pharmacology and Therapeutics, Roswell Park Cancer Inst., Elm and Carlton Sts., Buffalo, NY 14263. Tel.: 716-845-3002; Fax: 716-845-2353; E-mail: carl.porter{at}roswellpark.org.

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