Transcriptional regulation of microsomal prostaglandin E synthase 1 by the proto-oncogene, c-myc, in the pathogenesis of inflammation and cancer

• c-myc binds to three E-box elements in the promoter region of mPGES1 and induces the transcription of this gene.
• Mutation of the proximal c-myc binding site results in considerable decrease in the promoter activity.
• Transfection of increasing concentrations of c-myc increases the production of PGE2.
• Isocoumarin analogs and Licofelone inhibit the mRNA expressions of both c-myc and mPGES1 and the production of PGE2.

Pro-inflammatory molecules play a key role in the progression of various types of cancers highlighting the importance of studying the pathways that regulate the inflammatory cytokine production. To this end, prostaglandins have been reported to correlate with exacerbated cancer phenotypes that may be prevented by using anti-inflammatory drugs in humans. To understand how the prostaglandin E synthase 1 (mPGES1) may be regulated we analyzed its promoter sequence and identified myc-binding sites. Functional validation was performed by mutating the sites that led to attenuated promoter activation of mPGES1. The known c-myc inhibitor (10058-F4) also blocked PGE2 activity, indicating the importance of c-Myc in PGE2 synthesis. Isocoumarin analogs were able to reduce the expressions of both c-myc as well as mPGES1 and also inhibit the production of PGE2. Based on these data and the well-established role of c-myc in oncogenesis, we have demonstrated an additional role of c-myc in exacerbating cancers via PGE2 production, which may provide a therapeutic opportunity to treat these diseases.

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