title: The essential role of methylthioadenosine phosphorylase in prostate cancer.
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.
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Gaia
authors.initials: G
authors.lastname: Bistulfi
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Hayley C
authors.initials: HC
authors.lastname: Affronti
authors.affiliation: Department of Molecular Pharmacology and Cancer Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Foster
authors.affiliation: Department of Molecular Pharmacology and Cancer Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Karasik
authors.affiliation: Department of Molecular Pharmacology and Cancer Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Gillard
authors.affiliation: Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Morrison
authors.affiliation: Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: James
authors.initials: J
authors.lastname: Mohler
authors.affiliation: Department of Translational Hematology/Oncology Research, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Phillips
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Smiraglia
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008297:Male; D008715:Methionine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D011759:Pyrrolidines; C556837:methylthio-DADMe-immucillin-A; D008715:Methionine; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D000225:Adenine
keywords: methionine cycle; methionine salvage pathway; methylthioadenosine phosphorylase; polyamine metabolism; prostate cancer