Phosphorylation of PPARγ via active ERK1/2 leads to its physical association with p65 and inhibition of NF‐κβ

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Abstract
Peroxisome proliferator-activated receptors (PPAR) are novel nuclear receptors and PPARγ ligands have been shown to produce pro-apoptotic effects in many cancer cell types, including colon cancer. PPARγ ligands exert their effect through PPARγ-dependent (genomic) and PPARγ-independent (non-genomic) mechanisms. Recent evidence suggests that PPARγ ligands exert their pro-apoptotic effects in part by directly antagonizing the NF-κβ 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 PPARγ ligands induces HT-29 colon cancer cells to undergo apoptosis and prior to apoptosis, ciglitazone exposure results in a transient phosphorylation of PPARγ. This phosphorylation of PPARγ was mediated through the ciglitazone-induced activation of Erk1/2. PPARγ phosphorylation affected the genomic pathway by being inhibitory to PPARγ–DNA binding and PPRE transcriptional activity, as well as the non-genomic pathway by increasing the physical interaction of PPARγ with p65, leading to the inhibition of NF-κβ. Ciglitazone induced phosphorylation of PPARγ through the MAP kinase pathway provides a potential regulatory mechanism for PPARγ's physical interaction with p65, leading to inhibition of NF-κβ and subsequent apoptosis.

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