Bryostatin-1 stimulates the transcription of cyclooxygenase-2: evidence for an activator protein-1-dependent mechanism.
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.
De Lorenzo
Mariana S
MS
Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA.
Yamaguchi
Kentaro
K
Subbaramaiah
Kotha
K
Dannenberg
Andrew J
AJ
D000970:Antineoplastic Agents / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D054713:Bryostatins; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D007783:Lactones / Q000378:metabolism* / Q000494:pharmacology; D018942:Macrolides; D008264:Macrophages / Q000378:metabolism; D008565:Membrane Proteins; D008956:Models, Chemical; D008957:Models, Genetic; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014212:Tretinoin / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
D000970:Antineoplastic Agents; D054713:Bryostatins; D007527:Isoenzymes; D007783:Lactones; D018942:Macrolides; D008565:Membrane Proteins; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; C046785:bryostatin 1; D014212:Tretinoin; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D001616:beta-Galactosidase