title: Retinoids and carnosol suppress cyclooxygenase-2 transcription by CREB-binding protein/p300-dependent and -independent mechanisms.
abstract: Treatment with retinoic acid (RA) or carnosol, two structurally unrelated compounds with anticancer properties, inhibited phorbol ester (PMA)-mediated induction of activator protein-1 (AP-1) activity and cyclooxygenase-2 (COX-2) expression in human mammary epithelial cells. The induction of COX-2 transcription by PMA was mediated by increased binding of AP-1 to the cyclic AMP response element (CRE) of the COX-2 promoter. Inhibition of the histone acetyltransferase activity of CREB- binding protein (CBP)/p300 blocked the induction of COX-2 by PMA. Treatment with carnosol but not RA blocked increased binding of AP-1 to the COX-2 promoter. Because AP-1 binding was unaffected by RA, we investigated whether RA inhibited COX-2 transcription via effects on the coactivator CBP/p300. Treatment with RA stimulated an interaction between RA receptor-alpha and CBP/p300; a corresponding decrease in the interaction between CBP/p300 and c-Jun was observed. Importantly, overexpressing CBP/p300 or dominant-negative RA receptor-alpha relieved the suppressive effect of RA on PMA-mediated stimulation of the COX-2 promoter. To elucidate the mechanism by which carnosol inhibited COX-2 transcription, its effects on protein kinase C (PKC) signaling were determined. Carnosol but not RA inhibited the activation of PKC, ERK1/2, p38, and c-Jun NH2-terminal kinase mitogen-activated protein kinase. Overexpressing c-Jun but not CBP/p300 reversed the suppressive effect of carnosol on PMA-mediated stimulation of COX-2 promoter activity. Thus, RA acted by a receptor-dependent mechanism to limit the amount of CBP/p300 that was available for AP-1-mediated induction of COX-2. By contrast, carnosol inhibited the induction of COX-2 by blocking PKC signaling and thereby the binding of AP-1 to the CRE of the COX-2 promoter. Taken together, these results show that small molecules can block the activation of COX-2 transcription by distinct mechanisms.
authors: Department of Medicine, New York Presbyterian Hospital-Cornell and Strang Cancer Prevention Center, New York, New York 10021, USA. ksubba@med.cornell.edu
authors: Kotha
authors: K
authors: Subbaramaiah
authors: Philip A
authors: PA
authors: Cole
authors: Andrew J
authors: AJ
authors: Dannenberg
mesh_terms: D045784:Abietanes; D000123:Acetyltransferases / Q000037:antagonists & inhibitors / Q000502:physiology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D050882:CREB-Binding Protein; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D002461:Cell Line, Transformed; D051546:Cyclooxygenase 2; D004790:Enzyme Induction / Q000187:drug effects; D051548:Histone Acetyltransferases; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D008565:Membrane Proteins; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D010616:Phenanthrenes / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000502:physiology; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
chemical_list: D045784:Abietanes; D000123:Acetyltransferases; D016588:Anticarcinogenic Agents; D050882:CREB-Binding Protein; D018797:Cell Cycle Proteins; D051546:Cyclooxygenase 2; D051548:Histone Acetyltransferases; D007527:Isoenzymes; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010616:Phenanthrenes; D011451:Prostaglandin-Endoperoxide Synthases; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014212:Tretinoin; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C068623:carnosol; C496540:PTGS2 protein, human; C494363:CREBBP protein, human