Phosphorylation of PPARgamma via active ERK1/2 leads to its physical association with p65 and inhibition of NF-kappabeta.
Peroxisome proliferator-activated receptors (PPAR) are novel nuclear receptors and PPARgamma ligands have been shown to produce pro-apoptotic effects in many cancer cell types, including colon cancer. PPARgamma ligands exert their effect through PPARgamma-dependent (genomic) and PPARgamma-independent (non-genomic) mechanisms. Recent evidence suggests that PPARgamma ligands exert their pro-apoptotic effects in part by directly antagonizing the NF-kappabeta pathway as well as through activation of the MAP kinase pathway. In this report, we have demonstrated that ciglitazone, a member of the thiazoldinedione class of PPARgamma ligands induces HT-29 colon cancer cells to undergo apoptosis and prior to apoptosis, ciglitazone exposure results in a transient phosphorylation of PPARgamma. This phosphorylation of PPARgamma was mediated through the ciglitazone-induced activation of Erk1/2. PPARgamma phosphorylation affected the genomic pathway by being inhibitory to PPARgamma-DNA binding and PPRE transcriptional activity, as well as the non-genomic pathway by increasing the physical interaction of PPARgamma with p65, leading to the inhibition of NF-kappabeta. Ciglitazone induced phosphorylation of PPARgamma through the MAP kinase pathway provides a potential regulatory mechanism for PPARgamma's physical interaction with p65, leading to inhibition of NF-kappabeta and subsequent apoptosis.
Division of Surgical Oncology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, New Jersey 07103, USA.
Fei
F
Chen
Muchun
M
Wang
J Patrick
JP
O'Connor
Mai
M
He
Tushar
T
Tripathi
Lawrence E
LE
Harrison
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004247:DNA / Q000235:genetics / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D051996:Transcription Factor RelA; D014157:Transcription Factors; D004247:DNA; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C039671:ciglitazone