Cross-talk between Peroxisome Proliferator-Activated Receptor δ and Cytosolic Phospholipase A2α/Cyclooxygenase-2/Prostaglandin E2 Signaling Pathways in Human Hepatocellular Carcinoma Cells

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Abstract
Peroxisome proliferator-activated receptor δ (PPARδ) is a nuclear transcription factor that is recently implicated in tumorigenesis besides lipid metabolism. This study describes the cross-talk between the PPARδ and prostaglandin (PG) signaling pathways that coordinately regulate human hepatocellular carcinoma (HCC) cell growth. Activation of PPARδ by its pharmacologic ligand, GW501516, enhanced the growth of three human HCC cell lines (HuH7, HepG2, and Hep3B), whereas inhibition of PPARδ by small interfering RNA prevented growth. PPARδ activation up-regulates the expression of cyclooxygenase (COX)-2, a rate-limiting enzyme for PG synthesis, and tumor growth. PPARδ activation or PGE2 treatment also induced the phosphorylation of cytosolic phospholipase A2α (cPLA2α), a key enzyme that releases arachidonic acid substrate for PG production via COX. Activation of cPLA2α by the calcium ionophore A23187 enhanced PPARδ binding to PPARδ response element (DRE) and increased PPARδ reporter activity, which was blocked by the selective cPLA2α inhibitors. Consistent with this, addition of arachidonic acid to isolated nuclear extracts enhanced the binding of PPARδ to DRE in vitro, suggesting a direct role of arachidonic acid for PPARδ activation in the nucleus. Thus, PPARδ induces COX-2 expression and the COX-2–derived PGE2 further activates PPARδ via cPLA2α. Such an interaction forms a novel feed-forward growth-promoting signaling that may play a role in hepatocarcinogenesis. (Cancer Res 2006; 66(24): 11859-68)

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