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 PPARgamma ligands inhibit cell growth and induce apoptosis in colon cancer cells, the mechanism of these effects of PPARgamma ligands is unclear. In this report, we demonstrate that the PPARgamma ligand, ciglitazone, exhibits an anti-proliferative effect and blocks G1/S cell cycle progression through regulation of p27kip1 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 p27kip1. However, an increase in p27kip1 protein synthesis as evidenced by increased p27kip1 gene promoter activity and mRNA abundance was observed as early as 24 h after exposure to ciglitazone. Proteasome activity, an additional mechanism of p27kip1 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 p27kip1 protein levels which in turn is due a balance of ciglitazone's affect on new protein synthesis and degradation.
Chen
Fei
F
Department of Surgery, Division of Surgical Oncology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, MSB G524, Newark, NJ 07103, USA.
Harrison
Lawrence E
LE
D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D002352:Carrier Proteins / Q000819:agonists* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000819:agonists* / Q000235:genetics; D008024:Ligands; D047495:PPAR gamma / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D012333:RNA, Messenger / Q000819:agonists; D016196:S Phase / Q000187:drug effects; D044786:S-Phase Kinase-Associated Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D014158:Transcription, Genetic
C436291:CDKN1B protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D047495:PPAR gamma; D012333:RNA, Messenger; D044786:S-Phase Kinase-Associated Proteins; D045162:Thiazolidinediones; D050760:Cyclin-Dependent Kinase Inhibitor p27; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D046988:Proteasome Endopeptidase Complex; C039671:ciglitazone