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Br J Pharmacol. 2002 Jan;135(2):511-9.

Different glucocorticoids vary in their genomic and non-genomic mechanism of action in A549 cells.

Author information

1
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

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.

PMID:
11815387
PMCID:
PMC1573139
DOI:
10.1038/sj.bjp.0704474
[Indexed for MEDLINE]
Free PMC Article

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