Peroxisome Proliferator-Activated Receptor γ-Independent Repression of Prostate-Specific Antigen Expression by Thiazolidinediones in Prostate Cancer Cells

Abstract

In light of the potential use of the thiazolidinedione family of peroxisome proliferator-activated receptor-␥ (PPAR␥) agonists in prostate cancer treatment, this study assessed the mechanism by which these agents suppress prostate-specific antigen (PSA) secretion in prostate cancer cells. Two lines of evidence indicate that the effect of thiazolidinediones on PSA downregulation is independent of PPAR␥ activation. First, this thiazolidinedione-mediated PSA down-regulation is structure-specific irrespective of the relative PPAR␥ agonist potency. Second, the PPAR␥-inactive analogs of troglitazone and ciglitazone [⌬2TG (5-[4-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-yl-methoxy)-benzylidene]-thiazolidine-2,4-dione) and ⌬2CG (5-[4-(1-methyl-cyclohexylmethoxy)-benzylidene]-thiazolidine-2,4-dione), respectively] exhibit higher potency than the parent compound in inhibiting dihydrotestosterone (DHT)-stimulated PSA secretion. Although 10 M troglitazone and ⌬2TG 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 troglitazone and ⌬2TG block AR recruitment to the androgen response elements within the PSA promoter. Thus, this study raises the question of whether the ability of oral troglitazone to reduce PSA levels in prostate cancer patients is therapeutically relevant. A major concern is that the concentration for troglitazone to mediate antitumor effects is severalfold higher than that of PSA down-regulation, which is difficult to attain at therapeutic doses. Nevertheless, it is noteworthy that troglitazone and ⌬2TG at high doses were able to inhibit AR expression. From a translational perspective, separation of PPAR␥ agonist activity from AR down-regulation provides a molecular basis to use troglitazone as a platform to design AR-ablative agents.

A Potent Indole-3-Carbinol–Derived Antitumor Agent with Pleiotropic Effects on Multiple Signaling Pathways in Prostate Cancer Cells

“…The finding that many indole derivatives, including diindoylmethanes, exhibited PPARg agonist activity (18, 25-28, 36, 37) raised the possibility that PPARg activation might contribute to the apoptosis-inducing effect of OSU-A9. Accordingly, we used an established PPRE-luciferase reporter assay (33) to assess the ability of OSU-A9 to transactivate PPARg in PC-3 cells. However, even at 20 Amol/L, OSU-A9 lacked appreciable activity in PPARg transactivation, whereas the PPARg agonist rosiglitazone induced significant activation of the reporter gene (Fig.…”

“…The PPAR-response element (PPRE)-x3-TK-Luc reporter vector contains three copies of the PPRE upstream of the thymidine kinase promoter-luciferase fusion gene and was kindly provided by Dr. Bruce Spiegelman (Harvard University, Cambridge, MA). The reporter gene assay was carried out as previously described (33). In brief, PC-3 cells were cultured in a 100-mm plate in phenol red-free RPMI 1640 containing 10% FBS until the achieved 50% to 70% confluency, after which they were transfected with 6 Ag of the plasmid using Fugene 6 (Roche) in RPMI 1640.…”

Δ2-Troglitazone promotes cytostatic rather than pro-apoptotic effects in breast cancer cells cultured in high serum conditions

“…These results are in agreement with the study of Yang et al showing that 10 mM of D2-TGZ were sufficient to significantly reduce LNCaP prostate cancer cells viability after 24 h of treatment in serum-free conditions whereas no considerable effect was detected with up to 50 mM of D2-TGZ in 10% FCS conditions. 11 Thus, the reduced sensitivity of cells to D2-TGZ in high serum conditions is not restricted to breast cancer cells. Besides, a study reported that troglitazone, the parent molecule of D2-TGZ, activated the ERK pathway and induced p21 Cip/WAF1 in the colorectal cancer cell lines HCT15 and HT29 with a dose of 200 mM in 10% FBS-conditions, whereas 20 mM of TGZ were enough to induce these effects in 1% FBSconditions.…”

“…This attenuation of PPARg activity is explained by the structural rigidity induced by the double bond introduction surrounding the heterocycle system. 10,11 In breast cancer cell lines, the number of viable cells was reduced after exposure to D2-TGZ. 12 Such a treatment induced a proteasome-dependent proteolysis of both cyclin D1 and estrogen receptor a in hormone-dependent breast cancer cell lines.…”

Peroxisome Proliferator-Activated Receptor γ–Independent Suppression of Androgen Receptor Expression by Troglitazone Mechanism and Pharmacologic Exploitation

“…Previously, data from this and other laboratories indicate that the peroxisome proliferator-activated receptor-g (PPARg) agonist troglitazone might interfere with AR function through two PPARg-independent mechanisms (15,16). At concentrations f10 Amol/L, troglitazone and its PPARg-inactive derivative D2TG repressed prostate-specific antigen (PSA) through the inhibition of AR recruitment to the PSA promoter.…”