Activation of polyamine catabolism as a novel anticancer strategy for prostate cancer.

摘要

Depletion of intracellular polyamine pools invariably inhibits cell growth and thus, represents a viable therapeutic/prevention strategy. Although pool depletion is usually accomplished by inhibiting polyamine biosynthesis, we propose that this might be more effectively achieved by activation of the polyamine catabolism at the level of spermidine/spermine N 1-acetyltransferase (SSAT). Due to unique aspects of polyamine homeostasis in the prostate gland, tumor cells derived from it may be particularly sensitive to this approach. SSAT was conditionally overexpressed in LNCaP prostate carcinoma cells via a tetracycline-repressible system. Tetracycline removal resulted in a ∼20-fold increase in SSAT mRNA and enzyme activity and massive accumulation of the SSAT products N1-acetylspermidine (AcSpd), N1-acetylspermine and N1, N12-diacetylspermine. This, in turn, led to sustained growth inhibition that was not due to decrease in spermidine (Spd) and spermine (Spm) pools as anticipated, but rather to a compensatory increase in biosynthetic enzyme activities that resulted in a high rate of metabolic flux through both the biosynthetic and catabolic pathways.;We next examined the in vivo consequences of SSAT overexpression in mice 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 wk of age, the average genitourinary tract weights of TRAMP mice were ∼4 times larger than those of TRAMP/SSAT mice and by 36 wk, they were ∼12 times larger. SV40 large T-antigen expression in the prostate epithelium was similar in TRAMP and TRAMP/SSAT mice. Consistent with the 18-fold increase in SSAT activity in the TRAMP/SSAT bigenics, prostatic AcSpd and Put pools increased remarkably relative to the TRAMP mice. (Abstract shortened by UMI.).