Inhibition of dihydrotestosterone synthesis in prostate cancer by combined frontdoor and backdoor pathway blockade
- Oncotarget. 2018 Jan 10;9(13):11227-11242. doi: 10.18632/oncotarget.24107.
- 1. Department of Urology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
- 2. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
- 3. Department of Biostatistics and Bioinformatics Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
- 4. Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
- 5. Center for Pharmaceutical Research and Innovation and Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA.
- 6. Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
Androgen deprivation therapy (ADT) is palliative and Prostate Cancer (CaP) recurs as lethal castration-recurrent/resistant CaP (CRPC). One mechanism that provides CaP resistance to ADT is primary backdoor androgen metabolism, which uses up to four 3α-oxidoreductases to convert 5α-androstane-3α,17β-diol (DIOL) to dihydrotestosterone (DHT). The goal was to determine whether inhibition of 3α-oxidoreductase activity decreased conversion of DIOL to DHT. Protein sequence analysis showed that the four 3α-oxidoreductases have identical catalytic amino acid residues. Mass spectrometry data showed combined treatment using catalytically inactive 3α-oxidoreductase mutants and the 5α-reductase inhibitor, dutasteride, decreased DHT levels in CaP cells better than dutasteride alone. Combined blockade of frontdoor and backdoor pathways of DHT synthesis provides a therapeutic strategy to inhibit CRPC development and growth.