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

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.

Tadalafil and Steroid Hormones Interactions in Adipose, Bone and Prostate Tissues: Focus on Translational Perspectives

“…We demonstrated for the first time that tadalafil can modulate AR expression in prostate cancer cells in vitro. We also showed that tadalafil induces the stabilization and reduces the degradation of AR, that is more efficiently accumulated within the nucleus [30]. Interestingly, this effect could lead to a potential anti-cancer action of tadalafil by enhancing the therapeutic effect of ADT.…”

“…Moreover, in PCa cell lines, the AR antagonist bicalutamide (BCT) increased ARO expression and ERβ transcriptional activity; indeed, in CRPC ARO expression was significantly increased in tumor samples. Our study carried on with LnCAP cells, demonstrated for the first time that chronic exposure (48hrs) to BCT produced a significant increase in ARO mRNA, that was reverted by co-treatment with tadalafil [30]. The inhibition of PDE5 has been shown to induce anticancer effects [36] both in pre-clinical [37,38] and clinical experiences [39].…”

“…In this PCa cell-line, the acute exposure of LNCaP to tadalafil did not affect cell viability, as well as proliferation rate. Tadalafil upregulates AR protein expression and transcriptional activity, without affecting neither metabolism nor proliferation of PCa cells [30]. AR is the classical target for PCa prevention and treatment, but more recently estrogens and their receptors have also been implicated in both development and tumor progression.…”

“…We herein speculate that the local increase in estrogen levels might activate ERβ intracellular pathway and that chronic exposure to BCT may induce loss of ERβ due to induction of Cyp19a1. Tadalafil potentiated the antiproliferative activity of BCT in LnCAP cells [30] and co-treatment with tadalafil was able to block these effects, thus leading to hypothesize the maintenance of androgen responsiveness to anti-androgen therapy. (Fig.…”

The endocrine disruptor cadmium modulates the androgen-estrogen receptors ratio and induces inflammatory cytokines in luminal (A) cell models of breast cancer

“…RNA extraction was performed using TRIZOL according to the manufacturer's instructions, as previously described [22,23]. Treatment with DNAse enzyme was performed to remove genomic DNA contamination.…”