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Activation of Polymine Catabolism as a Novel Strategy for Treating and/or Preventing Human Prostate Cancer
HEALTH RESEARCH INC BUFFALO NY
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We proposed that activation of polyamine catabolism as opposed to inhibition of polyamine biosynthesis will have a therapeutic effect against prostate carcinoma. Thus, we found that a conditional overexpression of the polyamine catabolic enzyme spermidine spermine N1-acetyltransferase SSAT causes growth inhibition in LNCaP prostate carcinoma cells via a unique mechanism and b transgenic overexpression of SSAT in TRAMP mice markedly suppresses prostate tumor development. Both effects were found to occur via SSAT mediated metabolic flux through the polyamine pathway leading to depletion of the critical SSAT cofactor acetyl-CoA and interference with fat metabolism. Genetic deletion of SSAT had no effect on tumor development in the TRAMP mouse while heterozygous expression of the polyamine biosynthetic enzyme ornithine decarboxylase unexpectedly enhanced tumor growth while reducing tumor invasion into the seminal vesicles. Taken together, the findings suggest that a specific small molecule inducer of SSAT will suppress the development of prostate cancer.
APPROVED FOR PUBLIC RELEASE