Targeted inhibition of COX-2 expression by RNA interference suppresses tumor growth and potentiates chemosensitivity to cisplatin in human gastric cancer cells.

Abstract

Although selective cyclooxygenase-2 (COX-2) inhibitors suppress cell proliferation in gastric cancer, it remains debatable whether their effect is mediated through COX-2 dependent or independent pathways. We investigated the effects of the targeted inhibition of COX-2 expression by small interfering RNA (siRNA) in human gastric cancer cells and compared it to the effects of treatment with a specific COX-2 inhibitor. COX-2 mRNA and proteins were significantly reduced by up to 80% on day 2 after COX-2 siRNA transfection to the gastric cancer cell line MKN45. Concentrations of prostaglandins E2 (PGE2) in the condition medium were also reduced to 30% after siRNA transfection. Transfection of COX-2 siRNA exhibited a more potent anti-proliferative effect on MKN45 cells than treatment with high-dose (100 microM) NS398. COX-2 siRNA also significantly reduced tumor growth in nude mice. While COX-2 siRNA transfection alone had no obvious pro-apoptotic effects, unlike low-dose (10 microM) NS398 it enhanced the apoptotic reaction of MKN45 cells to cisplatin therapy. In conclusion, our results demonstrate for the first time that COX-2 siRNA inhibits cell growth and enhances the chemosensitivity of gastric cancer cells. RNA interference may be a promising alternative to specific COX-2 inhibitors in the prevention and treatment of gastric cancer.