Bryostatin-1 Stimulates the Transcription of Cyclooxygenase-2: Evidence for an Activator Protein-1-Dependent Mechanism Academic Article uri icon

Overview

MeSH Major

  • Isoenzymes
  • Lactones
  • Prostaglandin-Endoperoxide Synthases
  • Transcription Factor AP-1
  • Transcription, Genetic

abstract

  • Bryostatin-1 (bryostatin) is a macrocyclic lactone derived from Bugula neritina, a marine bryozoan. On the basis of the strength of in vitro and animal studies, bryostatin is being investigated as a possible treatment for a variety of human malignancies. Severe myalgias are a common dose-limiting side effect. Because cyclooxygenase-2 (COX-2)-derived prostaglandins can cause pain, we investigated whether bryostatin induced COX-2. Bryostatin (1-10 nM) induced COX-2 mRNA, COX-2 protein, and prostaglandin biosynthesis. These effects were observed in macrophages as well as in a series of human cancer cell lines. Transient transfections localized the stimulatory effects of bryostatin to the cyclic AMP response element of the COX-2 promoter. Electrophoretic mobility shift assays and supershift experiments revealed a marked increase in the binding of activator protein-1 (AP-1)(c-Jun/c-Fos) to the cyclic AMP response element of the COX-2 promoter. Pharmacological and transient transfection studies indicated that bryostatin stimulated COX-2 transcription via the protein kinase C-->mitogen-activated protein kinase-->AP-1 pathway. All-trans-retinoic acid, a prototypic AP-1 antagonist, blocked bryostatin-mediated induction of COX-2. Taken together, these results suggest that bryostatin-mediated induction of COX-2 can help to explain the myalgias that are commonly associated with treatment. Moreover, it will be worthwhile to evaluate whether the addition of a selective COX-2 inhibitor can increase the antitumor activity of bryostatin.

publication date

  • October 15, 2003

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed ID

  • 14581379

Additional Document Info

start page

  • 5036

end page

  • 43

volume

  • 9

number

  • 13