RETRACTED: Regulation of Wnt/β-catenin pathway by cPLA2α and PPARδ (Retracted article. See vol. 116, pg. 686, 2015)

Cytosolic phospholipase A(2)alpha (cPLA(2)alpha) 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)alpha 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)alpha in the nucleus remains unknown. Here we show a novel role of cPLA(2)alpha for activation of peroxisome proliferator-activated receptor-delta (PPAR delta) and beta-catenin in the nuclei. Overexpression of cPLA(2)alpha in human cholangiocarcinoma cells induced the binding of PPAR delta beta-catenin and increased their association with the TCF/LEF response element. These effects are inhibited by the cPLA(2)alpha siRNA and inhibitors as well as by siRNA knockdown of PPAR delta. Overexpression of PPAR delta or treatment with the selective PPAR delta ligand, GW501516, also increased beta-catenin binding to TCF/LFF response element and increased its reporter activity. Addition of AA and GW501516 to nuclear extracts induced a comparable degree of beta-catenin binding to TCF/LEF response element. Furthermore, cPLA(2)alpha protein is present in the PPAR delta and beta-catenin binding complex. Thus the close proximity between cPLA(2)alpha and PPAR delta provides a unique advantage for their efficient functional coupling in the nucleus, where AA produced by cPLA(2)alpha becomes immediately available for PPAR delta binding and subsequent beta-catenin activation. These results depict a novel interaction linking cPLA(2)alpha, PPAR delta and Wnt/beta-catenin signaling pathways and provide insight for further understanding the roles of these key molecules in human cells and diseases.