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J. Biol. Chem., Vol. 279, Issue 26, 27050-27058, June 25, 2004

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Metabolic and Antiproliferative Consequences of Activated Polyamine Catabolism in LNCaP Prostate Carcinoma Cells^*

Kristin Kee, Slavoljub Vujcic, Salim Merali, Paula Diegelman, Nicholas Kisiel, C. Thomas Powell¶, Debora L. Kramer, and Carl W. Porter||

From the Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263, the Department of Medical and Molecular Parasitology, New York University School of Medicine, New York, New York 10010, and the ^¶Cleveland Clinic Foundation, Lerner Research Institute, Cleveland, Ohio 44195

Depletion of intracellular polyamine pools invariably inhibits cell growth. Although this is usually accomplished by inhibiting polyamine biosynthesis, we reasoned that this might be more effectively achieved by activation of polyamine catabolism at the level of spermidine/spermine N¹-acetyltransferase (SSAT); a strategy first validated in MCF-7 breast carcinoma cells. We now examine the possibility that, due to unique aspects of polyamine homeostasis in the prostate gland, tumor cells derived from it may be particularly sensitive to activated polyamine catabolism. Thus, SSAT was conditionally overexpressed in LNCaP prostate carcinoma cells via a tetracycline-regulatable (Tet-off) system. Tetracycline removal resulted in a rapid 10-fold increase in SSAT mRNA and an increase of 20-fold in enzyme activity. SSAT products N¹-acetylspermidine, N¹-acetylspermine, and N¹,N¹²-diacetylspermine accumulated intracellularly and extracellularly. SSAT induction also led to a growth inhibition that was not accompanied by polyamine pool depletion as it was in MCF-7 cells. Rather, intracellular spermidine and spermine pools were maintained at or above control levels by a robust compensatory increase in ornithine decarboxylase and S-adenosylmethionine decarboxylase activities. This, in turn, gave rise to a high rate of metabolic flux through both the biosynthetic and catabolic arms of polyamine metabolism. Treatment with the biosynthesis inhibitor -difluoromethylornithine during tetracycline removal interrupted flux and prevented growth inhibition. Thus, flux-induced growth inhibition appears to derive from overaccumulation of metabolic products and/or from depletion of metabolic precursors. Metabolic effects that were not excluded as possible contributing factors include high levels of putrescine and acetylated polyamines, a 50% reduction in S-adenosylmethionine, and a 45% decline in the SSAT cofactor acetyl-CoA. Overall, the study demonstrates that activation of polyamine catabolism in LNCaP cells elicits a compensatory increase in polyamine biosynthesis and downstream metabolic events that culminate in growth inhibition.

Received for publication, March 25, 2004 , and in revised form, April 9, 2004.

^* This work was supported by NCI National Institutes of Health Grants CA-72648, CA-22153, CA-09072-30 and CA-16056 and by Department of Defense Award PC020638. 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 should be addressed. Tel.: 716-845-3002; Fax: 716-845-2353; E-mail: carl.porter{at}roswellpark.org.

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