Pharmacological polyamine catabolism upregulation with methionine salvage pathway inhibition as an effective prostate cancer therapy
| Autor: | Barbara A. Foster, Robert A. Casero, Mikhail A. Nikiforov, Anna Bianchi-Smiraglia, Gissou Azabdaftari, Mark D. Long, Hayley C. Affronti, Roberto Pili, Ellen Karasik, Justine J. Jacobi, Anthony J. Pellerite, Michael T. Moser, Kristopher Attwood, Dominic J. Smiraglia, Bryan Gillard, John Wilton, Aryn M. Rowsam, James G. Phillips, Christoph S. Boerlin, Spencer Rosario |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Pyrrolidines Cancer therapy Science General Physics and Astronomy Spermine Apoptosis Article General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences chemistry.chemical_compound Prostate cancer Methionine 0302 clinical medicine Downregulation and upregulation Acetyltransferases Cell Line Tumor Polyamines medicine Animals Humans lcsh:Science Salvage Therapy Mice Inbred BALB C Multidisciplinary Adenine Prostatic Neoplasms General Chemistry medicine.disease Cancer metabolism 3. Good health Spermidine Metabolic pathway Polyamine Catabolism 030104 developmental biology Purine-Nucleoside Phosphorylase chemistry 030220 oncology & carcinogenesis Cancer research lcsh:Q Drug Therapy Combination Flux (metabolism) |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-15 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Prostatic luminal epithelial cells secrete high levels of acetylated polyamines into the prostatic lumen, sensitizing them to perturbations of connected metabolic pathways. Enhanced flux is driven by spermidine/spermine N1-acetyltransferase (SSAT) activity, which acetylates polyamines leading to their secretion and drives biosynthetic demand. The methionine salvage pathway recycles one-carbon units lost to polyamine biosynthesis to the methionine cycle to overcome stress. Prostate cancer (CaP) relies on methylthioadenosine phosphorylase (MTAP), the rate-limiting enzyme, to relieve strain. Here, we show that inhibition of MTAP alongside SSAT upregulation is synergistic in androgen sensitive and castration recurrent CaP models in vitro and in vivo. The combination treatment increases apoptosis in radical prostatectomy ex vivo explant samples. This unique high metabolic flux through polyamine biosynthesis and connected one carbon metabolism in CaP creates a metabolic dependency. Enhancing this flux while simultaneously targeting this dependency in prostate cancer results in an effective therapeutic approach potentially translatable to the clinic. Prostate cancer cells depend on MTAP, the rate-limiting enzyme involved in the methionine salvage pathway, to cope with increased polyamine biosynthesis. Here, the authors show that inducing upregulation of polyamine biosynthesis and targeting MTAP synergize to increase apoptosis in prostate cancer cells. |
| Databáze: | OpenAIRE |
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