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

Abstract

Previously, we showed that the peroxisome proliferatoractivated receptor ; (PPAR;) agonist troglitazone at high doses was able to suppress androgen receptor (AR) expression in LNCaP prostate cancer cells independently of PPAR;. Pharmacologic exploitation of this finding led to STG28, a PPAR;-inactive analogue of troglitazone with substantially higher potency in AR repression. Considering the pivotal role of AR in prostate tumorigenesis, this study investigates the mechanism by which troglitazone and derivatives suppress AR expression in LNCaP cells. Reverse transcription-PCR and reporter gene assays indicate that this drug-induced AR repression occurs at both mRNA and protein levels. Evidence suggests that troglitazone and derivatives mediate the transcriptional repression of AR by facilitating the ubiquitindependent proteasomal degradation of the transcriptional factor Sp1. These agents also cause the proteolysis of two proteins that regulate Sp1-mediated transcription (i.e., the TATA-binding protein-associated factor TAF II 250 and cyclin D1). However, their involvement in the transcriptional repression of AR is refuted by the finding that small interfering RNA knockdown of these two regulatory proteins does not cause AR down-regulation. STG28 does not cause significant reduction in Sp1 or AR expression in normal prostate epithelial cells. This discriminatory effect underscores the differential susceptibility of malignant versus normal cells to the inhibitory effect of STG28 on cell viability. From a translational perspective, STG28 provides a proof of principle that potent AR-ablative agents could be developed through structural modifications of troglitazone. Moreover, as the control of Sp1 degradation remains unclear, STG28 represents a unique pharmacologic probe to investigate the ubiquitin-proteasome system that regulates Sp1 proteolysis.

Methyl 2-Cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate Is a Peroxisome Proliferator-Activated Receptor-γ Agonist That Induces Receptor-Independent Apoptosis in LNCaP Prostate Cancer Cells

“…The results indicate that ␤-CDODA-Me inhibits AR transcription without the parallel induction of inhibitory transacting factors. Recent studies suggest that AR down-regulation of a PPAR␥-inactive thiazolidinedione analog was due to down-regulation of Sp1 protein (Yang et al, 2007). Results in Fig.…”

Docosahexaenoic Acid Inhibits Superoxide Dismutase 1 Gene Transcription in Human Cancer Cells: The Involvement of Peroxisome Proliferator-Activated Receptor α and Hypoxia-Inducible Factor-2α Signaling

“…To understand whether PPAR␣ or PPAR␥ is involved in the inhibitory effect of DHA on SOD-1 gene expression, cells were treated with 20 M troglitazone, a PPAR␥ agonist (Adams et al, 1997), and 500 M clofibrate, a PPAR␣ agonist (Göttlicher et al, 1992), for 20 h. The concentrations of troglitazone and clofibrate were chosen based on previous studies (Canuto et al, 2003;Hashimoto et al, 2004;Yang et al, 2007). Luciferase activity assay indicated that clofibrate suppresses SOD-1 gene transcription, whereas troglitazone does not (Fig.…”

Thiazolidinediones/PPARγ agonists and fatty acid synthase inhibitors as an experimental combination therapy for prostate cancer

“…Multiple preclinical studies show anti-cancer effects of thiazolidinediones (TZDs) PPARÁ agonist ligands (2)(3)(4)(5)(6). In contrast, clinical studies suggest that TZDs are largely ineffective as monotherapeutic agents in treating PCa (7).…”