Phosphodiesterase Type-5 Inhibitor Tadalafil Modulates Steroid Hormones Signaling in a Prostate Cancer Cell Line.

Viviana M Bimonte,Richard G Pestell,Ambra Antonioni,Francesco Marampon,Antonio Aversa,Giovanni Vitale,Mariaignazia Curreli,Andrea Lenzi,Antonio Brunetti,Silvia Migliaccio,Simona Fittipaldi,Elisabetta Ferretti

doi:10.3390/ijms22020754

Abstract

Background: The androgen receptor (AR) plays a key role in normal prostate homeostasis and in prostate cancer (PCa) development, while the role of aromatase (Cyp19a1) is still unclear. We evaluated the effects of a treatment with Tadalafil (TAD) on both these proteins. Methods: Androgen-sensitive human PCa cell line (LnCAP) was incubated with/without TAD (10−6 M) and bicalutamide (BCT) (10−4 M) to evaluate a potential modulation on cell proliferation, protein and mRNA expression of Cyp19a, AR and estrogen receptor-β (ERβ), respectively. Results: TAD increased early AR nuclear translocation (p < 0.05, after 15 min of exposure), and increased AR transcriptional activity (p < 0.05) and protein expression (p < 0.05) after 24 h. Moreover, after 24 h this treatment upregulated Cyp19a1 and ERβ mRNA (p < 0.05 and p < 0.005 respectively) and led to an increase in protein expression of both after 48 h (p < 0.05). Interestingly, TAD counteracted Cyp19a1 stimulation induced by BCT (p < 0.05) but did not alter the effect induced by BCT on the AR protein expression. Conclusion: We demonstrate for the first time that TAD can significantly modulate AR expression and activity, Cyp19a1 and ERβ expression in PCa cells, suggesting a specific effect of these proteins. In addition, TAD potentiates the antiproliferative activity of BCT, opening a new clinical scenario in the treatment of PCa.

Highlights

Prostate cancer (PCa) is the leading cause of male cancer death in western countries with an increasing incidence in developing countries [1]
Since the half-life of androgen receptor (AR) protein in LNCaP cells, cultured in the absence of androgens, is approximately 3 h [34], we investigated whether TAD increased AR by a process of protein stabilization
The rising prostatic specific antigen (PSA) levels measured in prostate cancer (PCa) patients, who become resistant to androgen deprivation therapy (ADT), indicate that AR signaling remains an essential target for pharmacological intervention

Summary

Introduction

Prostate cancer (PCa) is the leading cause of male cancer death in western countries with an increasing incidence in developing countries [1]. ADT is invariably followed by the recurrence of castration-resistant prostate cancer (CRPC) with a disease relapse time within 12–18 months [6,7] These events occur even earlier by repressing AR expression with androgen deprivation [8] and are facilitated by ADT [9]. Methods: Androgen-sensitive human PCa cell line (LnCAP) was incubated with/without TAD (10−6 M) and bicalutamide (BCT) (10−4 M) to evaluate a potential modulation on cell proliferation, protein and mRNA expression of Cyp19a, AR and estrogen receptor-β (ERβ), respectively. Conclusion: We demonstrate for the first time that TAD can significantly modulate AR expression and activity, Cyp19a1 and ERβ expression in PCa cells, suggesting a specific effect of these proteins. TAD potentiates the antiproliferative activity of BCT, opening a new clinical scenario in the treatment of PCa

Objectives

Methods

Results

Discussion

Conclusion