Cyclooxygenase (COX) the rate-limiting enzyme in prostaglandin (PG) synthesis exists in two principle isoforms, COX-1 and COX-2. A considerable body of evidence implicates COX-2 (and hence PG) up-regulation as a major factor in carcinogenesis in many tissues. In previous work, we have determined that the half-life of COX-2 mRNA is significantly increased in cytokine-stimulated human and rat cells. The objective of this work was to determine the putative molecular mechanisms that operate in human COX-2 mRNA stabilization by p38 mitogen activated protein kinase (MAPK) in normal and prostate cancer cell lines. I show that COX-2 up-regulation in human prostate cancer cells is, in part, induced by the stabilization of the COX-2 mRNA transcript by p38 MAPK.

The human prostate cancer cell lines DU145 and PC3 were utilized in this study. I have determined that MAPK inhibitors down-regulate COX-2 mRNA levels in stimulated DU145 and PC-3 human prostate cancer cells but not in the normal prostate cell line, CRL2221. I found that DU145 cells treated with the specific p38 MAPK inhibitor, SB203580, showed significant decreases in COX-2 mRNA levels relative to the identically treated CRL2221 cells. In the present study, I also provide evidence that p38 MAPK pathway regulates stability of COX-2 mRNA and hence PG production in DU145 and PC3 cells. This inhibitory effect, however, is significantly less in CRL221 cells.