Abstract
Peroxisome proliferator-activated receptor (PPAR)-δ is a nuclear receptor implicated in lipid metabolism and obesity. Recent evidence suggests that PPAR-δ may also play a role in carcinogenesis. This study was designed to examine the potential effect of PPAR-δ on the growth of human cholangiocarcinoma cells. Western blot analysis showed that PPAR-δ is expressed in three human cholangiocarcinoma cell lines, CCLP1, SG231, and HuCCT1. Activation of PPAR-δ by its pharmacological ligand, GW501516, significantly increased the growth of all three human cholangiocarcinoma cells and this effect was dose- and time-dependent (1–200 nM at 24–72 hours). Consistent with this, overexpression of PPAR-δ increased cell growth whereas inhibition of PPAR-δ by siRNA prevented growth. Overexpression of PPAR-δ or treatment with GW501516 increased the expression of COX-2 and the PPAR-δ-induced cell growth was blocked by siRNA inhibition of COX-2, suggesting that COX-2 at least in part mediates PPAR-δ effect. Furthermore, PGE2 treatment induced the phosphorylation of cPLA2α, a key enzyme that releases arachidonic acid substrate for PG production by COX-2, and enhanced PPAR-δ-mediated gene transcription in CCLP1 cells. Overexpression of cPLA2α increased PPAR-δ reporter activity and enhanced the binding of PPAR-δ to its response element (DRE), indicating a direct role of cPLA2α for PPAR-δ activation. Taken together, our findings suggest that PPAR-δ enhances COX-2 expression in human cholangiocarcinoma cells and that the COX-2 derived PGE2 further activates PPAR-δ through phosphorylation of cPLA2α. This study reveals a positive feedback loop between COX-2-derived PGE2 and PPAR-δ that is important for cholangiocarcinoma growth and can be targeted for chemoprevention and treatment.
Published Version
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