Pharmacological polyamine catabolism upregulation with methionine salvage pathway inhibition as an effective prostate cancer therapy

Hayley C. Affronti, Aryn M. Rowsam, Anthony J. Pellerite, Spencer R. Rosario, Mark D. Long, Justine J. Jacobi, Anna Bianchi-Smiraglia, Christoph S. Boerlin, Bryan M. Gillard, Ellen Karasik, Barbara A. Foster, Michael Moser, John H. Wilton, Kristopher Attwood, Mikhail A. Nikiforov, Gissou Azabdaftari, Roberto Pili, James G. Phillips, Robert A. Casero and Dominic J. Smiraglia ()
Additional contact information
Hayley C. Affronti: Roswell Park Comprehensive Cancer Center
Aryn M. Rowsam: Roswell Park Comprehensive Cancer Center
Anthony J. Pellerite: Roswell Park Comprehensive Cancer Center
Spencer R. Rosario: Roswell Park Comprehensive Cancer Center
Mark D. Long: Roswell Park Comprehensive Cancer Center
Justine J. Jacobi: Roswell Park Comprehensive Cancer Center
Anna Bianchi-Smiraglia: Roswell Park Comprehensive Cancer Center
Christoph S. Boerlin: Roswell Park Comprehensive Cancer Center
Bryan M. Gillard: Roswell Park Comprehensive Cancer Center
Ellen Karasik: Roswell Park Comprehensive Cancer Center
Barbara A. Foster: Roswell Park Comprehensive Cancer Center
Michael Moser: Roswell Park Comprehensive Cancer Center
John H. Wilton: Roswell Park Comprehensive Cancer Center
Kristopher Attwood: Roswell Park Comprehensive Cancer Center
Mikhail A. Nikiforov: Roswell Park Comprehensive Cancer Center
Gissou Azabdaftari: Roswell Park Comprehensive Cancer Center
Roberto Pili: Indiana University
James G. Phillips: Taussig Cancer Institute, Cleveland Clinic
Robert A. Casero: Johns Hopkins University
Dominic J. Smiraglia: Roswell Park Comprehensive Cancer Center

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-019-13950-4

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