Cross-talk between peroxisome proliferator-activated receptor δ and cytosolic phospholipase A2α/cyclooxygenase-2/prostaglandin E2 signaling pathways in human hepatocellular carcinoma cells

Peroxisome proliferator-activated receptor delta (PPAR delta) is a nuclear transcription factor that is recently implicated in tumorigenesis besides lipid metabolism. This study describes the cross-talk between the PPAR delta and prostaglandin (PG) signaling pathways that coordinately regulate human hepatocellular carcinoma (HCC) cell growth. Activation of PPAR delta by its pharmacologic ligand, GW501516, enhanced the growth of three human HCC cell lines (HuH7, HepG2, and Hep3B), whereas inhibition of PPAR delta by small interfering PUNA prevented growth. PPAR delta activation up-regulates the expression of cyclooxygenase (COX)-2, a rate-limiting enzyme for PG svnthesis, and tumor growth. PPAR delta activation or PGE(2) treatment also induced the phosphorylation of cytosolic phospholipase A(2)alpha (cPLA(2)alpha), a key enzyme that releases arachidonic acid substrate for PG production via COX. Activation of cPLA2a by the calcium ionophore A23187 enhanced PPAR delta binding to PPAR delta response element (DRE) and increased PPAR delta reporter activity, which was blocked by the selective ePLA(2)alpha inhibitors. Consistent with this, addition of arachidonic acid to isolated nuclear extracts enhanced the binding of PPAR delta to DRE in vitro, suggesting a direct role of arachidonic acid for PPAR delta activation in the nucleus. Thus, PPAR delta induces COX-2 expression and the COX-2-derived PGE(2) further activates PPAIM via cPLA(2)alpha Such an interaction forms a novel feed-forward growthpromoting signaling that may play a role in hepatocarcinogenesis.