Retinoids suppress phorbol ester-mediated induction of cyclooxygenase-2.

Cyclooxygenase-2 expression is up-regulated in transformed cells and tumors. Because this enzyme catalyzes the synthesis of prostaglandins, strategies aimed at suppressing its expression may prove useful in preventing or treating cancer. We investigated the ability of retinoids to suppress phorbol ester-mediated induction of cyclooxygenase-2 in human oral epithelial cells. Treatment with phorbol myristate acetate (PMA) resulted in approximately a 3-fold increase in the production of prostaglandin E2 (PGE2). Retinoids [all-trans-retinoic acid (RA), 13-cis-RA, and retinyl acetate] markedly suppressed PMA-mediated increases in amounts of cyclooxygenase-2 (Cox-2) and the production of PGE2. Retinoids also suppressed the induction of Cox-2 mRNA by PMA. Nuclear run-offs revealed increased rates of Cox-2 transcription after treatment with PMA; this effect was inhibited by all-trans-RA. Transient transfection experiments showed that PMA caused about a 2-fold increase in Cox-2 promoter activity, an effect that was suppressed by all-trans-RA. Our data indicate that treatment of oral epithelial cells with PMA is associated with enhanced transcription of Cox-2 and increased production of PGE2. These effects of PMA were inhibited by retinoids.