The Dietary Isothiocyanate, Sulforaphane, Suppresses Microsomal Prostaglandin E Synthase 1 by Regulating Hypoxia‐inducible Factor 1 alpha

Prostaglandin E2 (PGE2) plays an important role in cancer cell proliferation and tumor development. In PGE 2 biosynthesis, cyclooxygenase‐2 (COX‐2) coverts arachidonic acid into prostaglandin H 2 (PGH 2 ), that can be isomerized to PGE 2 by microsomal prostaglandin E synthase 1 (mPGES‐1). Sulforaphane (1–isothiocyanato ‐4‐ methylsulfinyl‐butane), the major isothiocyanate in broccoli, is a potent cancer chemopreventive agent whose mechanisms of action are still poorly understood. In this study, we show that sulforaphane suppresses the production of PGE 2 in a concentration‐dependent manner. Expression of mPGES‐1 is attenuated by sulforaphane at the protein and mRNA levels in human lung cancer cells (A549) while the expression level of COX‐2 remains unchanged. We tested the effect of sulforaphane on transcription factor binding to the mPGES‐1 promoter, and found that sulforaphane specifically suppressed HIF‐1α occupancy of the mPGES‐1 promoter. This inhibition correlated with decreased presence of mRNA polymerase II on the promoter. Finally, we examined the protein and mRNA level of HIF‐1α in sulforaphane treated cells. We found that sulforaphane dose‐dependently inhibited HIF‐1α protein levels without altering the steady state level of HIF‐1α mRNA. Together these results indicate that sulforaphane reduces PGE 2 expression by regulating HIF‐1α protein stability leading to suppression of mPGES‐1 transcription.