期刊
ONCOTARGET
卷 7, 期 12, 页码 14380-14393出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.7486
关键词
prostate cancer; methionine salvage pathway; methionine cycle; methylthioadenosine phosphorylase; polyamine metabolism
资金
- American Institute for Cancer Research Fellowship
- American-Italian Cancer Foundation Fellowship
- Department Of Defense post-doctoral fellowship
- American Institute of Cancer Research grant [208739]
- National Cancer Institute (NCI) [R21 CA121216]
- NCI Cancer Center [CA016056]
- Roswell Park Alliance Foundation
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.
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