Peroxisome proliferator-activated receptor γ ligand inhibits cell growth and invasion of human pancreatic cancer cells

Background. Peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed in certain human cancers; ligand-induced PPARgamma activation can result in growth inhibition and differentiation in these cells. However, the precise mechanism for the antiproliferative effect of PPARgamma ligands is not entirely known. Aim of Study. The purpose of this study was to examine the effect of PPARgamma ligands on pancreatic cancer cell growth and invasiveness. Methods. The effect of two PPARgamma ligands, 15 deoxy-Delta(12,14) prostaglandin J(2), (15d-PGJ(2),) and ciglitazone, on the growth of four human pancreatic cancer cell lines (BxPC-3, MIA PaCa-2, Panc-1, and L3.6) was assessed. Expression of cell-cycle and apoptotic -related proteins was measured. Finally, the effect of 15d-PGJ(2) on pancreatic cancer cell invasiveness and matrix metalloproteinase expression was determined. Results. Both 15d-PGJ(2) and ciglitazone inhibited the growth of all four pancreatic cancer cell lines in a dose- and time-dependent fashion. Treatment of BxPC-3 cells with 15d-PGJ(2) resulted in a time-dependent' decrease in cyclin D1 expression associated with a concomitant induction of p21(waf1) and p27(kip1). In addition, 15d-PGJ(2) treatment induced apoptosis through activation of caspase-8, -9, and -3. Moreover, pancreatic cancer cell invasiveness was significantly suppressed after treatment with a nontoxic dose of 15d-PGJ(2) which was associated with a reduction of MMP-2 and MMP-9 protein levels and activity. Conclusions. These results demonstrate that PPARgamma ligands have the dual advantage of inhibiting pancreatic cancer cell growth while reducing the invasiveness of the tumor cells, suggesting a potential role for these agents in the adjuvant treatment of pancreatic cancer.