Peroxisome proliferator-activated receptor γ-independent repression of prostate-specific antigen expression by thiazolidinediones in prostate cancer cells

Chih Cheng Yang, Chia Yu Ku, Shuo Wei, Chung Wai Shiau, Chang-Shi Chen, Joseph J. Pinzone, Mathew D. Ringel, Ching Shih Chen

Research output: Contribution to journalArticle

28 Citations (Scopus)

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. Two lines of evidence indicate that the effect of thiazolidinediones on PSA down-regulation 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 analogs of troglitazone and ciglitazone [Δ2TG (5-[4-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-yl-methoxy)-benzylidene] -thiazolidine-2,4-dione) and Δ2CG (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 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 troglitazone and Δ2TG 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 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.

Original languageEnglish
Pages (from-to)1564-1570
Number of pages7
JournalMolecular Pharmacology
Volume69
Issue number5
DOIs
Publication statusPublished - 2006 May 1

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troglitazone
Thiazolidinediones
Peroxisome Proliferator-Activated Receptors
Prostate-Specific Antigen
Prostatic Neoplasms
Androgen Receptors
Down-Regulation
Dihydrotestosterone
Androgens
Chromans
Chromatin Immunoprecipitation
Response Elements
Reporter Genes

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Yang, Chih Cheng ; Ku, Chia Yu ; Wei, Shuo ; Shiau, Chung Wai ; Chen, Chang-Shi ; Pinzone, Joseph J. ; Ringel, Mathew D. ; Chen, Ching Shih. / Peroxisome proliferator-activated receptor γ-independent repression of prostate-specific antigen expression by thiazolidinediones in prostate cancer cells. In: Molecular Pharmacology. 2006 ; Vol. 69, No. 5. pp. 1564-1570.
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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. Two lines of evidence indicate that the effect of thiazolidinediones on PSA down-regulation 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 analogs of troglitazone and ciglitazone [Δ2TG (5-[4-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-yl-methoxy)-benzylidene] -thiazolidine-2,4-dione) and Δ2CG (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 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 troglitazone and Δ2TG 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 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.",
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Peroxisome proliferator-activated receptor γ-independent repression of prostate-specific antigen expression by thiazolidinediones in prostate cancer cells. / Yang, Chih Cheng; Ku, Chia Yu; Wei, Shuo; Shiau, Chung Wai; Chen, Chang-Shi; Pinzone, Joseph J.; Ringel, Mathew D.; Chen, Ching Shih.

In: Molecular Pharmacology, Vol. 69, No. 5, 01.05.2006, p. 1564-1570.

Research output: Contribution to journalArticle

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AU - Yang, Chih Cheng

AU - Ku, Chia Yu

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AU - Shiau, Chung Wai

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AU - Ringel, Mathew D.

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AB - 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. Two lines of evidence indicate that the effect of thiazolidinediones on PSA down-regulation 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 analogs of troglitazone and ciglitazone [Δ2TG (5-[4-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-yl-methoxy)-benzylidene] -thiazolidine-2,4-dione) and Δ2CG (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 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 troglitazone and Δ2TG 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 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.

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