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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Testosterone metabolites inhibit proliferation of castration- and therapy-resistant prostate cancer
Felix Bremmer1, Hubertus Jarry2, Valerie Unterkircher1
1Institute of Pathology, University Medical Center, Göttingen 37075, Germany.
Abstract:
Novel treatments for castration-resistant prostate cancer (CRPC) such as abiraterone acetate (AA) or enzalutamide effectively target the androgen pathway to arrest aberrant signalling and cell proliferation. Testosterone is able to inhibit tumour cell growth in CRPC. Estrogen receptor-beta (ERβ) binds the testosterone-metabolites 3β-androstanediol and 3α-androstanediol in parallel to the canonical estradiol. In the prostate it is widely accepted that ERβ regulates estrogen signalling, mediating anti-proliferative effects. We used the prostate cancer cell lines LNCaP, PC-3, VCaP, and the non-neoplastic BPH-1. VCaP cells were treated with 1 nmol/L testosterone over 20 passages, yielding the cell line VCaPrev, sensitive to hormone therapies. In contrast, LNCaP cells were grown for more than 100 passages yielding a high passage therapy resistant cell line (hiPLNCaP). VCaP and hiPLNCaP cell lines were treated with 5 μmol/L AA for more than 20 passages, respectively, generating the AA-tolerant-subtypes VCaPAA and hiPLNCaPAA. Cell lines were treated with testosterone, dihydrotestosterone (DHT), R1881, and the androgen-metabolites 3β-androstanediol and 3α-androstanediol. 3β-androstanediol or 3α-androstanediol significantly reduced proliferation in all cell lines except the BPH-1 and androgen receptor-negative PC-3 and markedly downregulated AR and estrogen receptor alpha (ERα). Whereas ERβ expression was increased in all cell lines except BPH-1 or PC-3. In summary, 3β-adiol or 3α-adiol, as well as DHT and R1881, significantly reduced tumour cell growth in CRPC cells. Thus, these compounds represent novel potential therapeutic approaches to overcome drug-resistance in CRPC, especially with regard to AR-V7 function in therapy resistance. Furthermore, these data confirm the tumour suppressor properties of ERβ in CRPC.
Insights
Testosterone metabolites, 3β-androstanediol and 3α-androstanediol, inhibit castration-resistant prostate cancer (CRPC) cell growth. These compounds, along with others, show promise for overcoming drug resistance in CRPC, highlighting estrogen receptor-beta
Area of Science:
- Oncology
- Endocrinology
- Molecular Biology
Background:
- Novel treatments for castration-resistant prostate cancer (CRPC), including abiraterone acetate (AA) and enzalutamide, target the androgen pathway.
- Testosterone and its metabolites, such as 3β-androstanediol and 3α-androstanediol, can inhibit CRPC cell growth.
- Estrogen receptor-beta (ERβ) binds testosterone metabolites and is implicated in mediating anti-proliferative effects in the prostate.
Purpose of the Study:
- To investigate the effects of testosterone and its metabolites on CRPC cell proliferation and drug resistance.
- To explore the role of ERβ in CRPC and its potential as a therapeutic target.
- To identify novel therapeutic approaches for overcoming drug resistance in CRPC, particularly concerning AR-V7 function.
Main Methods:
- Utilized established prostate cancer cell lines (LNCaP, PC-3, VCaP) and a non-neoplastic line (BPH-1).
- Developed hormone-sensitive and resistant cell line models, including VCaPrev, hiPLNCaP, VCaPAA, and hiPLNCaPAA.
- Treated cell lines with testosterone, dihydrotestosterone (DHT), R1881, 3β-androstanediol, and 3α-androstanediol, assessing proliferation and receptor expression.
Main Results:
- 3β-androstanediol and 3α-androstanediol significantly reduced proliferation in most CRPC cell lines, except BPH-1 and androgen receptor-negative PC-3.
- These metabolites markedly downregulated androgen receptor (AR) and estrogen receptor alpha (ERα) expression.
- ERβ expression was increased in CRPC cell lines, suggesting a tumor suppressor role.
Conclusions:
- Testosterone metabolites (3β-androstanediol, 3α-androstanediol), DHT, and R1881 demonstrate significant tumor cell growth inhibition in CRPC.
- These compounds represent potential novel therapeutics to overcome CRPC drug resistance, especially related to AR-V7.
- The findings confirm the tumor suppressor properties of ERβ in CRPC, suggesting its therapeutic relevance.
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