Thiazolidinediones modulate the expression of beta-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 gamma.
Considering the role of aberrant beta-catenin signaling in tumorigenesis, we investigated the mechanism by which the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist troglitazone facilitated beta-catenin down-regulation. We demonstrate that troglitazone and its more potent PPARgamma-inactive analogs Delta2TG and STG28 mediated the proteasomal degradation of beta-catenin in prostate cancer cells by up-regulating the expression of beta-transducin repeat-containing protein (beta-TrCP), an F-box component of the Skp1-Cul1-F-box protein E3 ubiquitin ligase. Evidence indicates that although small interfering RNA-mediated beta-TrCP knockdown protected cells against STG28-facilitated beta-catenin ablation, ectopic beta-TrCP expression enhanced the degradation. The involvement of beta-TrCP in beta-catenin degradation was also corroborated by the pull-down analysis and the concurrent down-regulation of known beta-TrCP substrates examined, including Wee1, Ikappabetaalpha, cdc25A, and nuclear factor-kappaB/p105. Furthermore, glycogen synthase kinase-3beta represented a key regulator in the effect of these thiazolidinedione derivatives on beta-catenin proteolysis even though these agents increased its phosphorylation level. It is noteworthy that this drug-induced beta-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 beta-catenin and beta-TrCP, suggesting the translation potential of using STG28 as a scaffold to develop more potent chemopreventive agents.
Wei
Shuo
S
Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
Lin
Li-Fang
LF
Yang
Chih-Cheng
CC
Wang
Yu-Chieh
YC
Chang
Geen-Dong
GD
Chen
Hungwen
H
Chen
Ching-Shih
CS
D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D005562:Formazans / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008297:Male; D047495:PPAR gamma / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D013778:Tetrazolium Salts / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D018797:Cell Cycle Proteins; C100318:Cullin 1; D044842:Cullin Proteins; D044783:F-Box Proteins; D005562:Formazans; D047495:PPAR gamma; D011993:Recombinant Fusion Proteins; D044786:S-Phase Kinase-Associated Proteins; D013778:Tetrazolium Salts; D045162:Thiazolidinediones; D051176:beta Catenin; C079782:MTT formazan; D044767:Ubiquitin-Protein Ligases; D005982:Glutathione Transferase