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Retinoids suppress phorbol ester-mediated induction of cyclooxygenase-2
J R Mestre1, K Subbaramaiah, P G Sacks
1Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.
Abstract:
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.
Insights
Retinoids can suppress cyclooxygenase-2 (Cox-2) and prostaglandin E2 (PGE2) production in oral epithelial cells. This finding suggests retinoids may help prevent or treat cancer by inhibiting Cox-2 expression.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Cyclooxygenase-2 (Cox-2) is upregulated in cancer and synthesizes prostaglandins, which can promote tumor growth.
- Targeting Cox-2 is a potential strategy for cancer prevention and treatment.
Purpose of the Study:
- To investigate the effect of retinoids on phorbol myristate acetate (PMA)-induced cyclooxygenase-2 (Cox-2) expression and prostaglandin E2 (PGE2) production in human oral epithelial cells.
Main Methods:
- Cells were treated with PMA and various retinoids (all-trans-retinoic acid, 13-cis-retinoic acid, retinyl acetate).
- Measurements included PGE2 production, Cox-2 protein and mRNA levels, Cox-2 gene transcription (nuclear run-offs), and Cox-2 promoter activity (transient transfection).
Main Results:
- PMA treatment increased PGE2 production by approximately 3-fold and Cox-2 expression.
- Retinoids significantly suppressed PMA-induced increases in PGE2 production, Cox-2 protein, and Cox-2 mRNA levels.
- Retinoids, particularly all-trans-retinoic acid, inhibited PMA-induced increases in Cox-2 gene transcription and promoter activity.
Conclusions:
- PMA upregulates Cox-2 transcription and enhances PGE2 production in oral epithelial cells.
- Retinoids effectively inhibit these PMA-induced effects, suggesting a potential role in cancer chemoprevention.