Microtubule-interfering agents stimulate the transcription of cyclooxygenase-2 - Evidence for involvement of ERK1/2 and p38 mitogen-activated proteinkinase pathways

We investigated whether microtubule-interfering agents (MIAs: taxol, colchi cine, nocodazole, vinblastine, vincristine, 17-beta-estradiol, 2-methoxyest radiol) altered cyclooxygenase-a (COX-2) expression in human mammary epithe lial cells. MIAs enhanced prostaglandin E-2 synthesis and increased levels of COX-2 protein and mRNA Nuclear run-off assays revealed increased rates o f COX-2 transcription after treatment with MIAs. Calphostin C, an inhibitor of protein kinase C, blocked the induction of COX-2 by MIAs. The stimulati on of COX-2 promoter activity by MIAs was inhibited by overexpressing domin ant negative forms of Rho and Raf-l. MIAs stimulated ERR, JNK, and p38 mito gen-activated protein kinases (MAPK); pharmacological inhibitors of MAPK ki nase and p38 MAPK blocked the induction of COX-2 by MIAs. Overexpressing do minant negative forms of ERK1 or p38 MAPK inhibited MIA-mediated activation of the COX-2 promoter. MIAs stimulated the binding of the activator protei n-1 transcription factor complex to the cyclic AMP response element in the COX-2 promoter. A dominant negative form of c-Jun inhibited the activation of the COX-2 promoter by MIAs. Additionally, cytochalasin D, an agent that inhibits actin polymerization, stimulated COX-2 transcription by the same s ignaling pathway as MIAs. Thus, microtubule or actin-interfering agents sti mulated MAPK signaling and activator protein-1 activity. This led, in turn, to induction of COX-2 gene expression via the cyclic AMP response element site in the COX-2 promoter.