Received for publication February 26, 2007.
Revised June 13, 2007.
Accepted for publication June 14, 2007.

Thiazolidinediones Modulate the Expression of -Catenin and Other Cell-Cycle Regulatory Proteins by Targeting the F-Box Proteins of SCF E3 Ubiquitin Ligase Independently of PPAR

Abstract

Considering the role of aberrant -catenin signaling in tumorigenesis, we investigated the mechanism by which the peroxisome proliferator-activated receptor (PPAR) agonist troglitazone facilitated -catenin downregulation. We demonstrate that troglitazone and its more potent PPAR-inactive analogues, 2TG and STG28, mediated the proteasomal degradation of -catenin in prostate cancer cells by up-regulating the expression of -TrCP, an F-box component of the SCF E3 ubiquitin ligase. Evidence indicates that while siRNA-mediated -TrCP knockdown protected cells against STG28-facilitated -catenin ablation, ectopic -TrCP expression enhanced the degradation. The involvement of -TrCP in -catenin degradation was also corroborated by the pull-down analysis and the concurrent down-regulation of known -TrCP substrates examined, including Wee1, IB, cdc25A, and NFB/p105. Furthermore, GSK3 represented a key regulator in the effect of these thiazolidinedione derivatives on -catenin proteolysis even though these agents increased its phosphorylation level. It is noteworthy that this drug-induced -TrCP upregulation was accompanied by the concomitant downregulation of Skp2 and Fbw7, thereby affecting many of the target proteins of these two F-box proteins (such as p27 and cyclin E). Consequently, 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 -catenin and -TrCP, suggesting the translation potential of using STG28 as a scaffold to develop more potent chemopreventive agents.

Key words: PPARs, Mechanisms of cell killing/apoptosis, Oncogenes, Tumor suppressors