Activation of Polyamine Catabolism as a Noel Strategy for Treating and/or Preventing Human Prostate Cancer

摘要

The relationship of polyamines to the prostate is unique among all tissues since, in addition to synthesizing these molecules for cell growth, the gland produces massive quantities for export into semen. It might, therefore, be expected that prostatic tumors could exhibit atypical polyamine-related regulatory responses. We propose that activation of polyamine catabolism may have unique therapeutic potential against prostate carcinoma. Thus far, we have validated this hypothesis by demonstrating that (a) conditional overexpression of the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase (SSAT) causes growth inhibition in LNCaP prostate carcinoma cells and (b) cross- breeding of SSAT transgenic mice with prostate cancer prone TRAMP mice markedly suppresses genitourinary tumor development via an apparent depletion of the SSAT cofactor acetyl-CoA. Depletion of the critical metabolite, acetyl-CoA, appears to be responsible for a selective effect on the prostate and prostate proliferative disease. The ultimate goal of these studies is to genetically validate the concept that small molecule induction of SSAT represents a promising anticancer strategy against prostate cancer and that it is worthy of small molecule discovery and development.