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

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.