Peroxisome Proliferator‐activated Receptor gamma‐Independent Repression of Prostate Specific Antigen by Troglitazone and its Derivatives in Prostate Cancer Cells

Abstract

In light of the potential use of the thiazolidinedione family of peroxisome proliferator-activated receptor-γ (PPARγ) agonists in prostate cancer treatment, this study assessed the mechanism by which these agents suppress prostate specific antigen (PSA) secretion in prostate cancer cells is independent of PPARγ activation. First, this thiazolidinedione-mediated PSA down-regulation is structure- specific irrespective of the relative PPARγ agonist potency. Second, the PPARγ-inactive analogues of troglitazone and ciglitazone (Δ2TG and Δ2CG, respectively) exhibit higher potency than the parent compound in inhibiting dihydrotestosterone (DHT)-stimulated PSA secretion. While 10 μM troglitazone and Δ2TG significantly inhibit PSA secretion, they do not alter the expression level of androgen receptor (AR) or interfere with DHT-activated nuclear translocation of AR. However, reporter gene and chromatin immunoprecipitation studies indicate that TG and Δ2TG block AR recruitment to the androgen response elements (AREs) within the PSA promoter. Thus, this study raises a question of whether the ability of oral troglitazone to reduce PSA levels in prostate cancer patients is therapeutically relevant. Furthermore, it is noteworthy that troglitazone and Δ2TG at high doses were able to inhibit AR expression. From a translational perspective, separation of PPARγ agonist activity from AR down-regulation provides a molecular basis to use troglitazone as a platform to design AR-ablative agents.