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Monday 01 July 2002

Ketoconazole suppresses prostaglandin E(2)-induced cyclooxygenase-2 expression in human epidermoid carcinoma A-431 cells.

By: Kanda N, Watanabe S.

J Invest Dermatol 2002 Jul;119(1):174-81

Cyclooxygenase-2 is a key enzyme in the conversion of arachidonic acid to prostaglandins. The overexpression of cyclooxygenase-2 has been reported in skin cancer cells, and may be involved in carcinogenesis. Prostaglandin E2, the end product of cyclooxygenase-2-induced catalysis, autoamplifies the cyclooxygenase-2 expression. It is suggested that an anti-mycotic drug, ketoconazole may inhibit carcinogenesis. We herein investigated if ketoconazole may inhibit prostaglandin E2-induced cyclooxygenase-2 expression in human epidermoid carcinoma A-431 cells. Ketoconazole suppressed prostaglandin E2-induced cyclooxygenase-2 protein and mRNA expression and promoter activation in A-431; the suppressive effects of ketoconazole were counteracted by cyclic adenosine monophosphate analog. Analyses using deleted or mutated cyclooxygenase-2 promoters revealed that cyclic adenosine monophosphate response element (- 59 to - 53 bp) on the promoter was involved in prostaglandin E2-induced stimulation and ketoconazole-induced inhibition of the promoter activity. Electrophoretic mobility shift assays indicated that cyclic adenosine monophosphate response element binding protein and activating transcription factor-1 may constitutively bind to cyclic adenosine monophosphate response element on cyclooxygenase-2 promoter. Prostaglandin E2 increased the proportion of phosphorylated forms among total bound cyclic adenosine monophosphate response element binding protein/activating transcription factor-1, and the effect was suppressed by ketoconazole. Prostaglandin E2 induced the phosphorylation of cyclic adenosine monophosphate response element binding protein and activating transcription factor-1, and the phosphorylation was suppressed by cyclic adenosine monophosphate-dependent protein kinase (protein kinase A) inhibitor, indicating protein kinase A-mediated phosphorylation. Ketoconazole suppressed the prostaglandin E2-induced phosphorylation of cyclic adenosine monophosphate response element binding protein/activating transcription factor-1. Prostaglandin E2 increased intracellular cyclic adenosine monophosphate level by activating adenylate cyclase in A-431, and the increase was suppressed by ketoconazole. These results suggest that ketoconazole may suppress prostaglandin E2-induced cyclooxygenase-2 expression by inhibiting the cyclic adenosine monophosphate signal in A-431, and stress its anti-cancer effect.

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