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Updated: May 10, 2026
Prostate Organoid Cultures as Tools to Translate Genotypes and Mutational Profiles to Pharmacological Responses
Published on: October 24, 2019
Prostate cancer cells differ in testosterone accumulation, dihydrotestosterone conversion, and androgen receptor
Yue Wu1, Alejandro Godoy, Faris Azzouni
1Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Background:
Blocking 5α-reductase-mediated testosterone conversion to dihydrotestosterone (DHT) with finasteride or dutasteride is the driving hypothesis behind two prostate cancer prevention trials. Factors affecting intracellular androgen levels and the androgen receptor (AR) signaling axis need to be examined systematically in order to fully understand the outcome of interventions using these drugs.
Methods:
The expression of three 5α-reductase isozymes, as determined by immunohistochemistry and qRT-PCR, was studied in five human prostate cancer cell lines. Intracellular testosterone and DHT were analyzed using mass spectrometry. A luciferase reporter assay and AR-regulated genes were used to evaluate the modulation of AR activity.
Results:
Prostate cancer cells were capable of accumulating testosterone to a level 15-50 times higher than that in the medium. The profile and expression of 5α-reductase isozymes did not predict the capacity to convert testosterone to DHT. Finasteride and dutasteride were able to depress testosterone uptake in addition to lowering intracellular DHT. The inhibition of AR activity following drug treatment often exceeded the expected response due to reduced availability of DHT. The ability to maintain high intracellular testosterone might compensate for the shortage of DHT.
Conclusions:
The biological effect of finasteride or dutasteride appears to be complex and may depend on the interplay of several factors, which include testosterone turnover, enzymology of DHT production, ability to use testosterone and DHT interchangeably, and propensity of cells for off-target AR inhibitory effect.
Insights
Finasteride and dutasteride lower dihydrotestosterone (DHT) but prostate cancer cells can maintain high testosterone levels. This complex interplay affects androgen receptor activity and prostate cancer outcomes.
Area of Science:
- Endocrinology
- Oncology
- Pharmacology
Background:
- Prostate cancer prevention trials utilize finasteride and dutasteride to block testosterone to dihydrotestosterone (DHT) conversion.
- Understanding intracellular androgen levels and androgen receptor (AR) signaling is crucial for interpreting these drug interventions.
Purpose of the Study:
- To systematically examine factors influencing intracellular androgens and AR signaling in prostate cancer cells.
- To evaluate the effects of finasteride and dutasteride on testosterone, DHT, and AR activity.
Main Methods:
- Investigated 5α-reductase isozyme expression in prostate cancer cell lines via immunohistochemistry and qRT-PCR.
- Quantified intracellular testosterone and DHT using mass spectrometry.
- Assessed AR activity modulation through luciferase reporter assays and analysis of AR-regulated genes.
Main Results:
- Prostate cancer cells accumulate intracellular testosterone significantly higher than extracellular levels.
- 5α-reductase isozyme profiles did not correlate with DHT conversion capacity.
- Finasteride and dutasteride reduced testosterone uptake and intracellular DHT, with AR inhibition exceeding expectations.
- High intracellular testosterone may compensate for DHT reduction, influencing AR activity.
Conclusions:
- The biological impact of finasteride and dutasteride is complex, involving testosterone turnover, DHT production enzymology, and interchangeable use of androgens.
- Off-target AR inhibitory effects and cellular compensation mechanisms contribute to treatment outcomes.
- Further research is needed to fully elucidate the mechanisms underlying these drug effects in prostate cancer.
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