Relationships Of Prostaglandin E-2 With Fatty Acid Concentrations And Gene Expression In Colon Of Individuals At Increased Risk Of Colon Cancer

PGE2 is a well-known biomarker for colon cancer risk. PGE2 is formed from arachidonic acid (AA) via cyclooxygenases (COX-1 and 2) and prostaglandin E synthases (PGES), whereas it is catabolized by15-PG dehydrogenase (HPGD). The objective was to understand inter-individual differences in PGE2 concentrations by evaluating the impact of substrate availability and expression of genes in the PGE2 pathway. Colon biopsies were obtained from individuals at high risk for colon cancer. Quantitative Real Time PCR was used to measure mRNA expression of genes in the PGE2pathway: COX-1 and 2, PGES-1 and 3, HPGD and PGE2 receptors 2 and 4. The most expressed genes were HPGD and COX-1. COX-1 was positively associated with PGE2. There was no association of PGE2 with the substrate AA or eicosapentaneoic acid. Saturated fatty acid (SFA), however, was positively associated with PGE2, and there was a trend for a negative association with monounsaturated fatty acids. The mechanism involved for the effects of SFA, a non-substrate fatty acid, on PGE2 production could involve the activation of toll-like receptors that in turn activate COX-1 or the allosteric regulation of COX-1 by SFA. Both SFA and COX-1 were significant positive predictors of PGE2 after controlling for NSAID use. These results are consistent with the targeting of COX-1 for colon cancer prevention in individuals at high risk. This differs from data supporting COX-2 as a target for prevention on animal models of colon carcinogenesis. Supported by NIH grant grants CA120381 and CA130810