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Cross-talk between Peroxisome Proliferator-Activated Receptor and Cytosolic Phospholipase A₂/Cyclooxygenase-2/Prostaglandin E₂ Signaling Pathways in Human Hepatocellular Carcinoma Cells

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Requests for reprints: Tong Wu, Department of Pathology, University of Pittsburgh School of Medicine, MUH E-740, 200 Lothrop Street, Pittsburgh, PA 15213. Phone: 412-647-9504; Fax: 412-647-5237; E-mail: wut{at}upmc.edu.

Peroxisome proliferator-activated receptor (PPAR) is a nuclear transcription factor that is recently implicated in tumorigenesis besides lipid metabolism. This study describes the cross-talk between the PPAR and prostaglandin (PG) signaling pathways that coordinately regulate human hepatocellular carcinoma (HCC) cell growth. Activation of PPAR by its pharmacologic ligand, GW501516, enhanced the growth of three human HCC cell lines (HuH7, HepG2, and Hep3B), whereas inhibition of PPAR by small interfering RNA prevented growth. PPAR activation up-regulates the expression of cyclooxygenase (COX)-2, a rate-limiting enzyme for PG synthesis, and tumor growth. PPAR activation or PGE₂ treatment also induced the phosphorylation of cytosolic phospholipase A₂ (cPLA₂), a key enzyme that releases arachidonic acid substrate for PG production via COX. Activation of cPLA₂ by the calcium ionophore A23187 enhanced PPAR binding to PPAR response element (DRE) and increased PPAR reporter activity, which was blocked by the selective cPLA₂ inhibitors. Consistent with this, addition of arachidonic acid to isolated nuclear extracts enhanced the binding of PPAR to DRE in vitro, suggesting a direct role of arachidonic acid for PPAR activation in the nucleus. Thus, PPAR induces COX-2 expression and the COX-2–derived PGE₂ further activates PPAR via cPLA₂. 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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