Abstract
Prostatic epithelial cells secrete high levels of acetylated polyamines into the prostatic lumen. This distinctive characteristic places added strain on the connected pathways, which are forced to increase metabolite production to maintain pools. The methionine salvage pathway recycles the one-carbon unit lost to polyamine biosynthesis back to the methionine cycle, allowing for replenishment of SAM pools providing a mechanism to help mitigate metabolic stress associated with high flux through these pathways. The rate-limiting enzyme involved in this process is methylthioadenosine phosphorylase (MTAP), which, although commonly deleted in many cancers, is protected in prostate cancer. We report near universal retention of MTAP expression in a panel of human prostate cancer cell lines as well as patient samples. Upon metabolic perturbation, prostate cancer cell lines upregulate MTAP and this correlates with recovery of SAM levels. Furthermore, in a mouse model of prostate cancer we find that both normal prostate and diseased prostate maintain higher SAM levels than other tissues, even under increased metabolic stress. Finally, we show that knockdown of MTAP, both genetically and pharmacologically, blocks androgen sensitive prostate cancer growth in vivo. Our findings strongly suggest that the methionine salvage pathway is a major player in homeostatic regulation of metabolite pools in prostate cancer due to their high level of flux through the polyamine biosynthetic pathway. Therefore, this pathway, and specifically the MTAP enzyme, is an attractive therapeutic target for prostate cancer.
Highlights
Prostate is a secretory gland that produces and secretes massive amounts of polyamines[1,2,3,4], ubiquitous molecules essential for cellular life
methylthioadenosine phosphorylase (MTAP) is the rate limiting enzyme involved in the methionine salvage pathway
The high degree of polyamine biosynthesis in prostate makes this salvage pathway critical because decarboxylation of SAM is necessary to provide the propylamine donor required for generating spermidine and spermine, which generates MTA as a by-product (Figure 1)
Summary
Prostate is a secretory gland that produces and secretes massive amounts of polyamines[1,2,3,4], ubiquitous molecules essential for cellular life. Polyamine biosynthesis is connected to both the methionine cycle and one-carbon metabolism (Figure 1), which are forced to increase metabolite production in order to maintain nucleotide and S-adenosylmethionine (SAM) pools, respectively [7,8,9]. This stress is enhanced in prostate cancer (CaP) due to increased polyamine biosynthesis, DNA synthesis, and proliferation [7,8,9]. The prostate produces approximately 10 times more polyamines compared to other tissues [1,2,3]
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