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

Br J Pharmacol. 2002 Jan;135(2):511-9. doi: 10.1038/sj.bjp.0704474.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arachidonic Acid / antagonists & inhibitors
  • Arachidonic Acid / metabolism
  • Cell Division / drug effects
  • Cell Division / physiology
  • Cyclooxygenase 2
  • Dexamethasone / pharmacology
  • Dinoprostone / antagonists & inhibitors
  • Dinoprostone / metabolism
  • Enzyme Activation / drug effects
  • Gene Expression Regulation, Enzymologic / drug effects
  • Glucocorticoids / pharmacology*
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / biosynthesis
  • Membrane Proteins
  • Phospholipases A / metabolism
  • Prostaglandin-Endoperoxide Synthases / biosynthesis
  • Signal Transduction / drug effects
  • Tumor Cells, Cultured / cytology
  • Tumor Cells, Cultured / drug effects*
  • Tumor Cells, Cultured / enzymology
  • Tumor Cells, Cultured / metabolism


  • Glucocorticoids
  • Isoenzymes
  • Membrane Proteins
  • Arachidonic Acid
  • Dexamethasone
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Phospholipases A
  • Dinoprostone