Oncotarget

Research Papers:

Testosterone metabolites inhibit proliferation of castration- and therapy-resistant prostate cancer

Felix Bremmer _, Hubertus Jarry, Valerie Unterkircher, Silke Kaulfuss, Peter Burfeind, Heinz-Joachim Radzun, Philipp Ströbel and Paul Thelen

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Oncotarget. 2018; 9:16951-16961. https://doi.org/10.18632/oncotarget.24763

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Abstract

Felix Bremmer1, Hubertus Jarry2, Valerie Unterkircher1, Silke Kaulfuss3, Peter Burfeind3, Heinz-Joachim Radzun4, Philipp Ströbel4 and Paul Thelen5

1Institute of Pathology, University Medical Center, Göttingen 37075, Germany

2Department of Experimental Endocrinology, University Medical Center, Göttingen 37075, Germany

3Institute of Human Genetics, University Medical Center, Göttingen 37073, Germany

4Institute of Pathology, University Medical Center, Göttingen 37075, Germany

5Department of Urology, University Medical Center, Göttingen 37075, Germany

Correspondence to:

Felix Bremmer, email: felix.bremmer@med.uni-goettingen.de

Keywords: castration resistant prostate cancer; AKR1C1; AKR1C2 and AKR1C3; 3a-androstendiol; 3b-androstendiol

Received: December 07, 2017     Accepted: February 27, 2018     Published: March 30, 2018

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.


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