Peroxisome proliferator-activated receptor gamma-independent repression of prostate-specific antigen expression by thiazolidinediones in prostate cancer cells.
In light of the potential use of the thiazolidinedione family of peroxisome proliferator-activated receptor-gamma (PPARgamma) 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 down-regulation is independent of PPARgamma activation. First, this thiazolidinedione-mediated PSA down-regulation is structure-specific irrespective of the relative PPARgamma agonist potency. Second, the PPARgamma-inactive analogs of troglitazone and ciglitazone [Delta2TG (5-[4-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-yl-methoxy)-benzylidene]-thiazolidine-2,4-dione) and Delta2CG (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 microM troglitazone and Delta2TG 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 Delta2TG 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 Delta2TG at high doses were able to inhibit AR expression. From a translational perspective, separation of PPARgamma agonist activity from AR down-regulation provides a molecular basis to use troglitazone as a platform to design AR-ablative agents.
Yang
Chih-Cheng
CC
Division of Medical Chemistry, College of Pharmacy, and Department of Internal Medicine, The Ohio State University, 336 L. M. Parks Hall, Columbus, OH 43210, USA.
Ku
Chia-Yu
CY
Wei
Shuo
S
Shiau
Chung-Wai
CW
Chen
Chang-Shi
CS
Pinzone
Joseph J
JJ
Ringel
Mathew D
MD
Chen
Ching-Shih
CS
D000818:Animals; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D047495:PPAR gamma / Q000502:physiology*; D000077205:Pioglitazone; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors / Q000235:genetics*; D011471:Prostatic Neoplasms; D045162:Thiazolidinediones / Q000494:pharmacology*; D014162:Transfection
D047495:PPAR gamma; D045162:Thiazolidinediones; D013196:Dihydrotestosterone; D017430:Prostate-Specific Antigen; C039671:ciglitazone; D000077205:Pioglitazone