Regulation of STAT3 pathway by cPLA2α and PPARδ

Abstract

Cytosolic phospholipase A2α (cPLA2α) is a rate‐limiting key enzyme that releases arachidonic acid (AA) from membrane phospholipid. This study shows a novel role of cPLA2α for activation of peroxisome proliferator‐activated receptor‐δ (PPARδ) and STAT3 in the nuclei. Overexpression of cPLA2α in human hepatocellular carcinoma cells (Hep3B) induced the binding of PPARδ to STAT3 response element through the release of transcriptional repressor Bcl‐6 and increased STAT3 reporter activity as determined by luciferease reporter activity assay. These effects are significantly inhibited by the cPLA2α siRNA and specific inhibitors (AACOCF3 and Pyrrolidine) as well as by siRNA knockdown of PPARδ. Overexpression of PPARδ or treatment with the selective PPARδ ligand, GW501516, also increased PPARdelta binding to STAT3 response element and increased STAT3 reporter activity. Addition of GW501516 to nuclear extracts induced a comparable degree of PPARδ binding to STAT3 response element. Moreover, overexpression of PPARδ or treatment with GW501516 upregulated the expression of Stat3 and its downstream anti‐apoptotic molecules including Mcl‐1, Survivin and Bcl‐XL. These results reveal a novel interaction linking cPLA2α, PPARδ and STAT3 signaling pathways in human hepatocellular carcinoma cells.