Received for publication September 28, 2004.
Revised December 22, 2004.
Accepted for publication January 13, 2005.

Peroxisome Proliferator-Activated Receptor -Independent Ablation of Cyclin D1 by Thiazolidenediones and Their Derivatives in Breast Cancer Cells

Abstract

In light of the clinical relevance of targeting cyclin D1 in breast cancer, we have investigated the mechanism underlying the effect of the peroxisome proliferator-activated receptor- (PPAR) agonists troglitazone (TG) and ciglitazone (CG) on cyclin D1 repression. We obtain evidence that the ability of high doses of TG and CG to repress cyclin D1 is independent of PPAR activation. PPAR-inactive TG and CG analogues (2-TG and 2-CG) are able to facilitate cyclin D1 ablation with potency similar to that of TG and CG in MCF-7 cells. Reverse transcription PCR shows that the mRNA level of cyclin D1 remains unaltered in drug-treated cells, indicating the repression is mediated at the posttranscriptional level. Moreover, the ablative effect of these agents is specific to cyclin D1 as the expression levels of many other cyclins and cyclin-dependent kinases examined remain unchanged after drug treatment. Our data indicate that TG- and 2-TG-induced cyclin D1 repression is mediated via proteasome-facilitated proteolysis as it is inhibited by different proteasome inhibitors, including MG132, lactacystin, and epoxomicin, and is preceded by increased ubiquitination. The dissociation of these two pharmacological activities, i.e., PPAR activation and cyclin D1 ablation, provides a molecular basis to use 2-TG as a scaffold to develop a novel class of cyclin D1-ablative agents. Accordingly, a series of 2-TG derivatives are synthesized. Among them, 2-TG-6 represents a structurally optimized agent with potency an-order-of-magnitude higher than that of 2-TG in cyclin D1 repression and MCF-7 cell growth inhibition.

Key words: PPARs, Mechanisms of cell killing/apoptosis

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