Sulforaphane Regulation of Microsomal Prostaglandin E Synthase 1 Pathway

Prostaglandin E2 (PGE2) plays an important role in cancer cell proliferation and tumor progression. PGE2 biosynthesis involves cyclooxygenase-2 (COX-2) dependent coversion of arachidonic acid into prostaglandin H2 (PGH2) that is then isomerized to PGE2 by microsomal prostaglandin E synthase 1 (mPGES-1). We hypothesized that sulforaphane (SFN), a potent cancer chemopreventive agent, may control cancer in part through interfering with PGE2 synthesis in cancer cells. Studying the human lung carcinoma A549 cell line we found that SFN suppressed the production of PGE2 in a concentrationdependent manner. While COX-2 was inhibited at early time periods, its expression was restored by 24 hours. In contrast, expression of mPGES-1 was stably attenuated by SFN at the protein and mRNA level. SFN blocked transcription of the mPGES-1 gene by specifically suppressing hypoxia-inducible factor 1 alpha (HIF-1) and mRNA polymerase II (Pol II) occupancy of the mPGES-1 promoter. The reduction in HIF-1-directed transcription activity was accompanied by a reduction in HIF-1 protein following SFN treatment, but HIF- 1 mRNA level was unchanged. As well, studies using the proteasome inhibitor MG132 demonstrated that SFN does not alter proline hydroxylation or VHLdependent degradation of HIF-1. Instead, using exogenous expression vectors and bicistronic reporter vectors, we found that SFN inhibition of HIF-1 translation was dependent on internal ribosome entry site (IRES) sequences in the 5' untranslated portion of the HIF-1 mRNA.

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