Regulation of cyclooxgenase-2 mRNA stability by taxanes: Evidence for involvement of p38, MAPKAPK-2, and HuR

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′k-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-α 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.