Related Experiment Video
Updated: May 6, 2026
Murine Prostate Micro-dissection and Surgical Castration
Published on: May 11, 2016
5α-reductase type 3 enzyme in benign and malignant prostate
Mark A Titus1, Yun Li, Olga G Kozyreva
1Department of Urology, Roswell Park Cancer Institute, Buffalo, New York.
Background:
Currently available 5α-reductase inhibitors are not completely effective for treatment of benign prostate enlargement, prevention of prostate cancer (CaP), or treatment of advanced castration-recurrent (CR) CaP. We tested the hypothesis that a novel 5α-reductase, 5α-reductase-3, contributes to residual androgen metabolism, especially in CR-CaP.
Methods:
A new protein with potential 5α-reducing activity was expressed in CHO-K1 cellsandTOP10 E. coli for characterization. Protein lysates and total mRNA were isolated from preclinical and clinical tissues. Androgen metabolism was assessed using androgen precursors and thin layer chromatography or liquid chromatography tandem mass spectrometry.
Results:
The relative mRNA expression for the three 5α-reductase enzymes in clinical samples of CR-CaP was 5α-reductase-3 ≫ 5α-reductase-1> 5α-reductase-2. Recombinant 5α-reductase-3 protein incubations converted testosterone, 4-androstene-3,17-dione (androstenedione) and 4-pregnene-3,20-dione (progesterone) to dihydrotestosterone, 5α-androstan-3,17-dione, and 5α-pregnan-3,20-dione, respectively. 5α-Reduced androgen metabolites were measurable in lysates from androgen-stimulated (AS) CWR22 and CR-CWR22 tumors and clinical specimens of AS-CaP and CR-CaP pre-incubated with dutasteride (a bi-specific inhibitor of 5α-reductase-1 and 2).
Conclusion:
Human prostate tissues contain a third 5α-reductase that was inhibited poorly by dutasteride at high androgen substrate concentration in vitro, and it may promote DHT formation in vivo, through alternative androgen metabolism pathways when testosterone levels are low.
Insights
A newly identified third 5α-reductase enzyme contributes to androgen metabolism in prostate cancer. This enzyme is poorly inhibited by current treatments, suggesting it may drive disease progression, especially in castration-recurrent prostate cancer.
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.
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