Abstract
Cytosolic phospholipase A~2~α (cPLA~2~α) is a rate‐limiting key enzyme that releases arachidonic acid (AA) from membrane phospholipid for the production of biologically active lipid mediators including prostaglandins, leukotrienes and platelet‐activating factor. cPLA~2~α is translocated to nuclear envelope in response to intracellular calcium increase and the enzyme is also present inside the cell nucleus; however, the biological function of cPLA~2~α in the nucleus remains unknown. Here we show a novel role of cPLA~2~α for activation of peroxisome proliferator‐activated receptor‐δ (PPARδ) and β‐catenin in the nuclei. Overexpression of cPLA~2~α in human cholangiocarcinoma cells induced the binding of PPARδ to β‐catenin and increased their association with the TCF/LEF response element. These effects are inhibited by the cPLA~2~α siRNA and inhibitors as well as by siRNA knockdown of PPARδ. Overexpression of PPARδ or treatment with the selective PPARδ ligand, GW501516, also increased β‐catenin binding to TCF/LEF response element and increased its reporter activity. Addition of AA and GW501516 to nuclear extracts induced a comparable degree of β‐catenin binding to TCF/LEF response element. Furthermore, cPLA~2~α protein is present in the PPARδ and β‐catenin binding complex. Thus the close proximity between cPLA~2~α and PPARδ provides a unique advantage for their efficient functional coupling in the nucleus, where AA produced by cPLA~2~α becomes immediately available for PPARδ binding and subsequent β‐catenin activation. These results depict a novel interaction linking cPLA~2~α, PPARδ and Wnt/β‐catenin signaling pathways and provide insight for further understanding the roles of these key molecules in human cells and diseases. J. Cell. Biochem. 105: 534–545, 2008. © 2008 Wiley‐Liss, Inc.