Dimethylcelecoxib inhibits mPGES-1 promoter activity by influencing EGR1 and NF-κB

Abstract

DMC (dimethylcelecoxib={4-[5-(2,5-dimethylphenyl)-3(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide}) is a close derivative of celecoxib, without cyclooxygenase inhibiting properties up to very high concentrations. Nevertheless, after stimulation of various human cell lines with IL-1β/TNFα and simultaneous treatment with DMC PGE(2) synthesis is inhibited [1]. Here we investigated the effect of DMC on mPGES-1 promoter activity, using a reporter gene assay. Our data demonstrate that DMC inhibits mPGES-1 promoter activity by blocking nuclear EGR1 expression and repressing NF-κB transcriptional activity. Other putative transcription factors, known to regulate mPGES-1 expression, such as SP1 or CREB are not affected by DMC. Over-expression of EGR1 completely prevents the inhibitory effect of DMC on mPGES-1 promoter activity, indicating that the repressing effect of DMC on mPGES-1 expression is mainly dependent on blocking EGR1 expression. mPGES-1, EGR1 and NF-κB are important proteins involved in many pathological conditions such as inflammation and cancer. Therefore, DMC seems to be a promising substance to treat inflammatory and carcinogenic processes, although it does not inhibit cyclooxygenases.