A new molecular mechanism for blockade of prostaglandin E2 expression by sulforaphane

Abstract

Molecular mechanisms for cancer prevention by sulforaphane (SFN) are becoming known. We hypothesized that Prostaglandin E2 (PGE2), an inflammatory lipid that promotes cancer cell proliferation and tumor progression, may control cancer in part through interfering with PGE2 synthesis in cancer cells.SFN suppressed PGE2 expression in the human lung carcinoma cell line A549, and in A549 xenograft tumors in mice. Only transient suppression of cyclooxygenase‐2 (COX‐2) was detected. In contrast, SFN blocked transcription of the microsomal PGE2 synthase (mPGES‐1) gene by blocking hypoxia‐inducible factor 1 alpha (HIF‐1α) mediated transcription of mPGES‐1. HIF‐1α itself was reduced at the protein but not mRNA level. Loss of HIF‐1α protein was not a result of HIF‐1α protein destabilization. Instead, SFN inhibition of HIF‐1α translation was dependent on internal ribosome entry site (IRES) sequences in the 5′ untranslated portion of the HIF‐1α mRNA.These results demonstrate a new mechanism through which SFN can reduce PGE2 synthesis, through IRES‐dependent inhibition of HIF‐1α protein expression and suppression of mPGES1.This work was supported by NIH grants R01AT004323 (JVC) and R01CA113899 (DJT).