title: Peroxisome proliferator-activated receptor gamma-independent suppression of androgen receptor expression by troglitazone mechanism and pharmacologic exploitation.
abstract: Previously, we showed that the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist troglitazone at high doses was able to suppress androgen receptor (AR) expression in LNCaP prostate cancer cells independently of PPARgamma. Pharmacologic exploitation of this finding led to STG28, a PPARgamma-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 ubiquitin-dependent 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.
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA. chen.844@osu.edu
authors.forename: Chih-Cheng
authors.initials: CC
authors.lastname: Yang
authors.forename: Yu-Chieh
authors.initials: YC
authors.lastname: Wang
authors.forename: Shuo
authors.initials: S
authors.lastname: Wei
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Lin
authors.forename: Chang-Shi
authors.initials: CS
authors.lastname: Chen
authors.forename: Cheng-Chun
authors.initials: CC
authors.lastname: Lee
authors.forename: Cheng-Chieh
authors.initials: CC
authors.lastname: Lin
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
mesh_terms: D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology; D045744:Cell Line, Tumor; D002839:Chromans / Q000494:pharmacology*; D006801:Humans; D008297:Male; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D045162:Thiazolidinediones / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D000077288:Troglitazone
chemical_list: C513003:5-(4-((6-(allyloxy)-2,5,7,8-tetramethylchroman-2-yl)methoxy)-3-methoxybenzylidene)thiazolidine-2,4-dione; D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D001578:Benzopyrans; D002839:Chromans; D047495:PPAR gamma; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D016329:Sp1 Transcription Factor; D045162:Thiazolidinediones; D000077288:Troglitazone