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Abstract

Although prostate cancer can be clinically managed in its early phases, the inability to control the more aggressive late-stage disease has prompted the search for novel therapies. We hypothesize that strategies targeting polyamine homeostasis may be effective against prostate cancer. The prostate has the highest level of polyamine biosynthesis of any tissue, and it is the only tissue in which polyamines are purposely synthesized for export. In particular, large amounts of polyamines are excreted by the prostate into semen. Thus, we reasoned that polyamine homeostasis may be altered in the prostate relative to other tissues and that tumors derived from this gland may exhibit atypical regulatory responses in order to synthesize large amounts of polyamines in this tissue. Intracellular levels of polyamines are homeostatically maintained by effector systems controlling the biosynthesis, uptake and export of these molecules. By acetylating polyamines, the enzyme spermidine/spermine N1-acetyltransferase (SSAT) controls polyamine inactivation and export. Specifically, SSAT catalyzes the transfer of acetyl groups from acetyl-coenzyme A (acetyl-CoA) onto intracellular polyamines and thereby marks them for export and/or catabolism, which reduces their positive charge, blocks biological activity, promotes degradation, and facilitates excretion. We showed that in prostate tumors, overexpression of SSAT leads to futile metabolic cycling (polyamine flux). Furthermore, our and others studies have shown that overexpression of SSAT in transgenic mice (SSAT-tg) increased energy expenditure, which produced a polyamine-based cycle, reduced the levels of acetyl-CoA, increased glycolytic enzyme expression and decreased lactate production. These proof of principle studies provided evidence for linking the polyamine flux to the Warburg effect. Additional studies in prostate tumor cell lines have shown that the polyamine flux increases the glucose uptake, thereby creating the possibility of improved positron emission tomography (PET) with 18-fluorodeoxyglucose (FDG) because this imaging is not currently possible in prostate cancers. To further study the effect of polyamine flux on tumor growth in vivo, our transgenic mice were crossed with TRAMP mice (TRansgenic Adenocarcinoma of Mouse Prostate) to produce a bigenic mouse line (TRAMP/SSAT). These mice showed an increased in polyamine flux and importantly a reduction in prostate tumor burden. This novel approach for treating cancer by targeting a key regulator of cancer metabolism may provide a better, more efficient treatment for prostate cancer and improved PET imaging.

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/content/papers/10.5339/qfarc.2014.HBPP0429
2014-11-18
2020-09-22
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