Ciglitazone-induced cellular anti-proliferation increases p27kip1 protein levels through both increased transcriptional activity and inhibition of proteasome degradation

While it is well established that PPAR gamma ligands inhibit cell growth and induce apoptosis in colon cancer cells, the mechanism of these effects of PPAR gamma ligands is unclear. In this report, we demonstrate that the PPAR gamma ligand, ciglitazone, exhibits an anti-proliferative effect and blocks G1/S cell cycle progression through regulation of p27(kip1) protein levels and inhibition of Cdk2 activity in HT-29 colon cancer cells. The ciglitazone-induced G1/S cell cycle arrest was noted only after 72 h of exposure, corresponding to elevated protein levels of p27(kip1). However, an increase in p27(kip1) protein synthesis as evidenced by increased p27(kip1) gene promoter activity and mRNA abundance was observed as early as 24 It after exposure to ciglitazone. Proteasome activity, an additional mechanism of p27(kip1) regulation, was dramatically inhibited after ciglitazone exposure, but only after 72 h of exposure. We also note that the effects of ciglitazone on p27kip1 gene regulation are PPRE independent. These data suggest that ciglitazone-induced G1/S arrest is through Cdk2 inhibition and an increase of p27(kip1) protein levels which in turn is due a balance of ciglitazone's affect on new protein synthesis and degradation. (c) 2004 Elsevier Inc. All rights reserved.