The essential role of methylthioadenosine phosphorylase in prostate cancer

Oncotarget
Gaia BistulfiDominic J Smiraglia

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 prostat...Continue Reading

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Methods Mentioned

BETA
acetylates
xenografts
Transgenic
xenograft
Assay

Related Concepts

5'-Methylthioadenosine phosphorylase
methylthio-DADMe-immucillin-A
Adenine
Carcinoma, Cribriform
Metazoa
Pedameth
Mice, Inbred C57BL
Founder Mice, Transgenic
Malignant Neoplasm of Prostate
Nicotinamide Riboside Phosphorylase

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