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, Dominic J. Smiraglia

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number52
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Affronti, H. C., Rowsam, A. M., Pellerite, A. J., Rosario, S. R., Long, M. D., Jacobi, J. J., Bianchi-Smiraglia, A., Boerlin, C. S., Gillard, B. M., Karasik, E., Foster, B. A., Moser, M., Wilton, J. H., Attwood, K., Nikiforov, M. A., Azabdaftari, G., Pili, R., Phillips, J. G., Casero, R. A., & Smiraglia, D. J. (2020). Pharmacological polyamine catabolism upregulation with methionine salvage pathway inhibition as an effective prostate cancer therapy. Nature communications, 11(1), [52]. https://doi.org/10.1038/s41467-019-13950-4