Oncotarget

Research Papers:

Inhibition of dihydrotestosterone synthesis in prostate cancer by combined frontdoor and backdoor pathway blockade

Michael V. Fiandalo _, John J. Stocking, Elena A. Pop, John H. Wilton, Krystin M. Mantione, Yun Li, Kristopher M. Attwood, Gissou Azabdaftari, Yue Wu, David S. Watt, Elizabeth M. Wilson and James L. Mohler

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Oncotarget. 2018; 9:11227-11242. https://doi.org/10.18632/oncotarget.24107

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Abstract

Michael V. Fiandalo1, John J. Stocking1, Elena A. Pop1, John H. Wilton1,2, Krystin M. Mantione2, Yun Li1, Kristopher M. Attwood3, Gissou Azabdaftari4, Yue Wu1, David S. Watt5, Elizabeth M. Wilson6 and James L. Mohler1

1Department of Urology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA

2Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA

3Department of Biostatistics and Bioinformatics Roswell Park Cancer Institute, Buffalo, NY 14263, USA

4Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA

5Center for Pharmaceutical Research and Innovation and Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA

6Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA

Correspondence to:

James L. Mohler, email: [email protected]

Keywords: androstanediol; dihydrotestosterone; dutasteride; 3α-oxidoreductases; androgen deprivation therapy

Received: September 06, 2017     Accepted: November 19, 2017     Published: January 10, 2018

ABSTRACT

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.


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