5α-reductase type 3 enzyme in benign and malignant prostate

Area of Science:

• Endocrinology
• Oncology
• Biochemistry

Background:

• Current 5α-reductase inhibitors show limited efficacy in treating benign prostate enlargement, preventing prostate cancer (CaP), and managing advanced castration-recurrent (CR) CaP.
• A novel 5α-reductase, termed 5α-reductase-3, was investigated for its potential role in residual androgen metabolism, particularly in CR-CaP.

Purpose of the Study:

• To investigate the contribution of a novel 5α-reductase (5α-reductase-3) to androgen metabolism.
• To assess the efficacy of existing inhibitors against this new enzyme in prostate cancer models.

Main Methods:

• Expression and characterization of recombinant 5α-reductase-3 protein.
• Isolation of protein lysates and mRNA from preclinical and clinical prostate tissues.
• Assessment of androgen metabolism using androgen precursors and advanced chromatography techniques (TLC, LC-MS/MS).

Main Results:

• Relative mRNA expression in CR-CaP tissues showed 5α-reductase-3 >> 5α-reductase-1 > 5α-reductase-2.
• Recombinant 5α-reductase-3 converted testosterone, androstenedione, and progesterone to their respective 5α-reduced metabolites.
• 5α-reduced metabolites were detected in prostate cancer tissues, even after pre-incubation with dutasteride.

Conclusions:

• Human prostate tissues harbor a third 5α-reductase (5α-reductase-3).
• This enzyme is poorly inhibited by dutasteride at high androgen concentrations in vitro.
• 5α-reductase-3 may facilitate dihydrotestosterone (DHT) formation in vivo via alternative pathways, particularly when testosterone levels are low, potentially driving CR-CaP progression.