title: Different glucocorticoids vary in their genomic and non-genomic mechanism of action in A549 cells.
abstract: We have examined the effects of 12 glucocorticoids as inhibitors of A549 cell growth. Other than cortisone and prednisone, all the glucocorticoids inhibited cell growth and this was strongly correlated (r=0.91) with inhibition of prostaglandin (PG)E(2) formation. The molecular mechanism by which the active steroids prevented PGE(2) synthesis was examined and three groups were identified. Group A drugs did not inhibit arachidonic acid release but inhibited the induction of COX2. Group B drugs were not able to inhibit the induction of COX2 but inhibited arachidonic acid release through suppression of cPLA(2) activation. Group C drugs were apparently able to bring about both effects. The inhibitory actions of all steroids was dependent upon glucocorticoid receptor occupation since RU486 reversed their effects. However, group A acted through the NF-kappaB pathway to inhibit COX2 as the response was blocked by the inhibitor geldanamycin which prevents dissociation of GR and the effect was blocked by APDC, the NF-kappaB inhibitor. On the other hand, the group B drugs were not inhibited by NF-kappaB inhibitors or geldanamycin but their effect was abolished by the src inhibitor PP2. Group C drugs depended on both pathways. In terms of PGE(2) generation, there is clear evidence of two entirely separate mechanisms of glucocorticoid action, one of which correlates with NF-kappaB mediated genomic actions whilst the other, depends upon rapid effects on a cell signalling system which does not require dissociation of GR. The implications for these findings are discussed.
authors.affiliation: Department of Biochemical Pharmacology, The William Harvey Research Institute, St. Bartholomew's and the Royal London School of Medicine & Dentistry (Queen Mary and Westfield College), Charterhouse Square, London EC1M 6BQ. J.Croxtall@qmul.ac.uk
authors.forename: Jamie D
authors.initials: JD
authors.lastname: Croxtall
authors.forename: Peter Th W
authors.initials: PT
authors.lastname: van Hal
authors.forename: Qam
authors.initials: Q
authors.lastname: Choudhury
authors.forename: Derek W
authors.initials: DW
authors.lastname: Gilroy
authors.forename: Rod J
authors.initials: RJ
authors.lastname: Flower
mesh_terms: D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D051546:Cyclooxygenase 2; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008565:Membrane Proteins; D010741:Phospholipases A / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D007527:Isoenzymes; D008565:Membrane Proteins; D016718:Arachidonic Acid; D003907:Dexamethasone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D015232:Dinoprostone