Evaluation of eicosanoids and NSAIDs as PPARγ ligands in colorectal carcinoma cells

Abstract

The activation of peroxisome proliferator activated receptor γ (PPARγ) may play a role in the control of colorectal carcinogenesis. The expression of PPARγ was examined by Western blotting in human colorectal tumors and matched normal adjacent tissues, as well as in various colorectal carcinoma cell lines. In the tissues, the expression of PPARγ was elevated in tumors relative to the adjacent normal tissues. Each colorectal carcinoma cell line expressed PPARγ. The ability of various eicosanoids to bind PPARγ in colorectal carcinoma cells was investigated using luciferase reporter assays. The well-known PPARγ ligands, troglitazone and 15-deoxy-Δ^12,14-prostaglandin J₂ strongly induced PPARγ binding activity. Products of lipoxygenases displayed moderate binding activity, while other prostaglandins and fatty acids displayed little or no reporter activation. The activation of PPARγ by 13(S)-HODE, the major metabolite of 15-lipoxygenase-1 from linoleic acid, was concentration dependent reaching maximum at 10 μM (35-fold activation). The endogenous production of 13(S)-HODE by expression of 15-LO-1 did not activate PPARγ. The ability of various nonsteroidal anti-inflammatory drugs (NSAIDs) to induce PPARγ activation was also evaluated. The conventional NSAIDs that inhibit both cyclooxygenases (COX-1 and COX-2) also induced PPARγ binding activity. In general, however, neither COX-1- nor COX-2-specific inhibitors induced the activation of PPARγ. Taken together, the metabolites of 15-lipoxygenase and the conventional NSAIDs were confirmed as exogenous ligands for PPARγ in colorectal carcinoma cells.