Thiazolidinediones modulate the expression of β-catenin and other cell-cycle regulatory proteins by targeting the F-box proteins of Skp1-Cul1-F-box protein E3 ubiquitin ligase independently of peroxisome proliferator-activated receptor γ

Shuo Wei, Li Fang Lin, Chih Cheng Yang, Yu-Chieh Wang, Geen Dong Chang, Hungwen Chen, Ching Shih Chen

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Considering the role of aberrant β-catenin signaling in tumorigenesis, we investigated the mechanism by which the peroxisome proliferator-activated receptor γ (PPARγ) agonist troglitazone facilitated β-catenin down-regulation. We demonstrate that troglitazone and its more potent PPARγ-inactive analogs Δ2TG and STG28 mediated the proteasomal degradation of β-catenin in prostate cancer cells by up-regulating the expression of β-transducin repeat-containing protein (β-TrCP), an F-box component of the Skp1-Cul1-F-box protein E3 ubiquitin ligase. Evidence indicates that although small interfering RNA-mediated β-TrCP knockdown protected cells against STG28-facilitated β-catenin ablation, ectopic β-TrCP expression enhanced the degradation. The involvement of β-TrCP in β-catenin degradation was also corroborated by the pull-down analysis and the concurrent down-regulation of known β-TrCP substrates examined, including Wee1, Iκβα, cdc25A, and nuclear factor-κB/p105. Furthermore, glycogen synthase kinase-3β represented a key regulator in the effect of these thiazolidinedione derivatives on β-catenin proteolysis even though these agents increased its phosphorylation level. It is noteworthy that this drug-induced β-TrCP up-regulation was accompanied by the concomitant down-regulation of Skp2 and Fbw7, thereby affecting many of the target proteins of these two F-box proteins (such as p27 and cyclin E). As a consequence, the ability of troglitazone to target these F-box proteins provides a molecular basis to account for its reported effect on modulating the expression of aforementioned cell-cycle regulatory proteins. Despite this complicated mode of pharmacological actions, normal prostate epithelial cells, relative to LNCaP cells, were less susceptible to the effects of STG28 on modulating the expression of β-catenin and β-TrCP, suggesting the translation potential of using STG28 as a scaffold to develop more potent chemopreventive agents.

Original languageEnglish
Pages (from-to)725-733
Number of pages9
JournalMolecular Pharmacology
Volume72
Issue number3
DOIs
StatePublished - 1 Sep 2007

Fingerprint

F-Box Proteins
Thiazolidinediones
Catenins
Cell Cycle Proteins
Peroxisome Proliferator-Activated Receptors
Ubiquitin-Protein Ligases
Protein Transport
troglitazone
Down-Regulation
NFI Transcription Factors
Transducin
Glycogen Synthase Kinase 3
Cyclin E
Small Interfering RNA
Proteolysis
Prostate
Prostatic Neoplasms
Carcinogenesis
Up-Regulation
Epithelial Cells

Cite this

@article{31c56e72de71463f945cd006eb6b1e66,
title = "Thiazolidinediones modulate the expression of β-catenin and other cell-cycle regulatory proteins by targeting the F-box proteins of Skp1-Cul1-F-box protein E3 ubiquitin ligase independently of peroxisome proliferator-activated receptor γ",
abstract = "Considering the role of aberrant β-catenin signaling in tumorigenesis, we investigated the mechanism by which the peroxisome proliferator-activated receptor γ (PPARγ) agonist troglitazone facilitated β-catenin down-regulation. We demonstrate that troglitazone and its more potent PPARγ-inactive analogs Δ2TG and STG28 mediated the proteasomal degradation of β-catenin in prostate cancer cells by up-regulating the expression of β-transducin repeat-containing protein (β-TrCP), an F-box component of the Skp1-Cul1-F-box protein E3 ubiquitin ligase. Evidence indicates that although small interfering RNA-mediated β-TrCP knockdown protected cells against STG28-facilitated β-catenin ablation, ectopic β-TrCP expression enhanced the degradation. The involvement of β-TrCP in β-catenin degradation was also corroborated by the pull-down analysis and the concurrent down-regulation of known β-TrCP substrates examined, including Wee1, Iκβα, cdc25A, and nuclear factor-κB/p105. Furthermore, glycogen synthase kinase-3β represented a key regulator in the effect of these thiazolidinedione derivatives on β-catenin proteolysis even though these agents increased its phosphorylation level. It is noteworthy that this drug-induced β-TrCP up-regulation was accompanied by the concomitant down-regulation of Skp2 and Fbw7, thereby affecting many of the target proteins of these two F-box proteins (such as p27 and cyclin E). As a consequence, the ability of troglitazone to target these F-box proteins provides a molecular basis to account for its reported effect on modulating the expression of aforementioned cell-cycle regulatory proteins. Despite this complicated mode of pharmacological actions, normal prostate epithelial cells, relative to LNCaP cells, were less susceptible to the effects of STG28 on modulating the expression of β-catenin and β-TrCP, suggesting the translation potential of using STG28 as a scaffold to develop more potent chemopreventive agents.",
author = "Shuo Wei and Lin, {Li Fang} and Yang, {Chih Cheng} and Yu-Chieh Wang and Chang, {Geen Dong} and Hungwen Chen and Chen, {Ching Shih}",
year = "2007",
month = "9",
day = "1",
doi = "10.1124/mol.107.035287",
language = "English",
volume = "72",
pages = "725--733",
journal = "Molecular Pharmacology",
issn = "0026-895X",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

Thiazolidinediones modulate the expression of β-catenin and other cell-cycle regulatory proteins by targeting the F-box proteins of Skp1-Cul1-F-box protein E3 ubiquitin ligase independently of peroxisome proliferator-activated receptor γ. / Wei, Shuo; Lin, Li Fang; Yang, Chih Cheng; Wang, Yu-Chieh; Chang, Geen Dong; Chen, Hungwen; Chen, Ching Shih.

In: Molecular Pharmacology, Vol. 72, No. 3, 01.09.2007, p. 725-733.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Thiazolidinediones modulate the expression of β-catenin and other cell-cycle regulatory proteins by targeting the F-box proteins of Skp1-Cul1-F-box protein E3 ubiquitin ligase independently of peroxisome proliferator-activated receptor γ

AU - Wei, Shuo

AU - Lin, Li Fang

AU - Yang, Chih Cheng

AU - Wang, Yu-Chieh

AU - Chang, Geen Dong

AU - Chen, Hungwen

AU - Chen, Ching Shih

PY - 2007/9/1

Y1 - 2007/9/1

N2 - Considering the role of aberrant β-catenin signaling in tumorigenesis, we investigated the mechanism by which the peroxisome proliferator-activated receptor γ (PPARγ) agonist troglitazone facilitated β-catenin down-regulation. We demonstrate that troglitazone and its more potent PPARγ-inactive analogs Δ2TG and STG28 mediated the proteasomal degradation of β-catenin in prostate cancer cells by up-regulating the expression of β-transducin repeat-containing protein (β-TrCP), an F-box component of the Skp1-Cul1-F-box protein E3 ubiquitin ligase. Evidence indicates that although small interfering RNA-mediated β-TrCP knockdown protected cells against STG28-facilitated β-catenin ablation, ectopic β-TrCP expression enhanced the degradation. The involvement of β-TrCP in β-catenin degradation was also corroborated by the pull-down analysis and the concurrent down-regulation of known β-TrCP substrates examined, including Wee1, Iκβα, cdc25A, and nuclear factor-κB/p105. Furthermore, glycogen synthase kinase-3β represented a key regulator in the effect of these thiazolidinedione derivatives on β-catenin proteolysis even though these agents increased its phosphorylation level. It is noteworthy that this drug-induced β-TrCP up-regulation was accompanied by the concomitant down-regulation of Skp2 and Fbw7, thereby affecting many of the target proteins of these two F-box proteins (such as p27 and cyclin E). As a consequence, the ability of troglitazone to target these F-box proteins provides a molecular basis to account for its reported effect on modulating the expression of aforementioned cell-cycle regulatory proteins. Despite this complicated mode of pharmacological actions, normal prostate epithelial cells, relative to LNCaP cells, were less susceptible to the effects of STG28 on modulating the expression of β-catenin and β-TrCP, suggesting the translation potential of using STG28 as a scaffold to develop more potent chemopreventive agents.

AB - Considering the role of aberrant β-catenin signaling in tumorigenesis, we investigated the mechanism by which the peroxisome proliferator-activated receptor γ (PPARγ) agonist troglitazone facilitated β-catenin down-regulation. We demonstrate that troglitazone and its more potent PPARγ-inactive analogs Δ2TG and STG28 mediated the proteasomal degradation of β-catenin in prostate cancer cells by up-regulating the expression of β-transducin repeat-containing protein (β-TrCP), an F-box component of the Skp1-Cul1-F-box protein E3 ubiquitin ligase. Evidence indicates that although small interfering RNA-mediated β-TrCP knockdown protected cells against STG28-facilitated β-catenin ablation, ectopic β-TrCP expression enhanced the degradation. The involvement of β-TrCP in β-catenin degradation was also corroborated by the pull-down analysis and the concurrent down-regulation of known β-TrCP substrates examined, including Wee1, Iκβα, cdc25A, and nuclear factor-κB/p105. Furthermore, glycogen synthase kinase-3β represented a key regulator in the effect of these thiazolidinedione derivatives on β-catenin proteolysis even though these agents increased its phosphorylation level. It is noteworthy that this drug-induced β-TrCP up-regulation was accompanied by the concomitant down-regulation of Skp2 and Fbw7, thereby affecting many of the target proteins of these two F-box proteins (such as p27 and cyclin E). As a consequence, the ability of troglitazone to target these F-box proteins provides a molecular basis to account for its reported effect on modulating the expression of aforementioned cell-cycle regulatory proteins. Despite this complicated mode of pharmacological actions, normal prostate epithelial cells, relative to LNCaP cells, were less susceptible to the effects of STG28 on modulating the expression of β-catenin and β-TrCP, suggesting the translation potential of using STG28 as a scaffold to develop more potent chemopreventive agents.

UR - http://www.scopus.com/inward/record.url?scp=34548306411&partnerID=8YFLogxK

U2 - 10.1124/mol.107.035287

DO - 10.1124/mol.107.035287

M3 - Article

C2 - 17569795

AN - SCOPUS:34548306411

VL - 72

SP - 725

EP - 733

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 3

ER -