Regulation of Cyclooxgenase-2 mRNA Stability by Taxanes

Abstract

Taxanes are widely used to treat malignancies and are known to modulate the transcription of several genes. We investigated the effects of taxanes (docetaxel and paclitaxel) on cyclooxygenase-2 (COX-2) transcription and mRNA stability in human mammary epithelial cells. As reported previously for paclitaxel, docetaxel stimulated COX-2 transcription by an AP-1-dependent mechanism. Treatment with taxanes also enhanced the stability of COX-2 mRNA. To define the mechanism by which taxanes stabilized COX-2 mRNA, transient transfections were carried out using luciferase expression constructs containing the COX-2 3'-untranslated region (3'-untranslated region (UTR)). The stabilizing effects of taxanes were localized to the AU-rich region of COX-2 3'-UTR. RNA binding studies indicated that taxanes stimulated the binding of HuR to the AU-rich region of the COX-2 3'-UTR. Overexpression of antisense HuR suppressed taxane-mediated induction of COX-2 3'-UTR activity. We next investigated the signal transduction pathway responsible for taxane-mediated induction of COX-2. Taxanes enhanced protein kinase C activity; overexpressing dominant negative PKC-alpha suppressed taxane-mediated stimulation of both COX-2 3'-UTR and 5'-promoter activities. Interestingly, ERK1/2, JNK, and p38 MAPKs were important for taxane-mediated activation of COX-2 transcription, but only p38 MAPK appeared to be responsible for the increase in COX-2 mRNA stability. MAPKAPK-2, a known target of p38 MAPK, contributed to increased COX-2 mRNA stability following taxane treatment. SB 202190, a selective p38 MAPK inhibitor, and dexamethasone suppressed taxane-mediated stimulation of the COX-2 3'-UTR and binding of HuR. Taken together, these data indicate that taxanes induce COX-2 by stimulating both transcription and mRNA stability. To the best of our knowledge, this is the first evidence that taxanes can promote stabilization of mRNA in addition to modulating gene transcription.