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

Abstract

1 We have examined the e ects of 12 glucocorticoids as inhibitors of A549 cell growth. 2 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. 3 The molecular mechanism by which the active steroids prevented PGE 2 synthesis was examined and three groups were identi®ed. 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 e ects. 4 The inhibitory actions of all steroids was dependent upon glucocorticoid receptor occupation since RU486 reversed their e ects. However, group A acted through the NF-kB pathway to inhibit COX2 as the response was blocked by the inhibitor geldanamycin which prevents dissociation of GR and the e ect was blocked by APDC, the NF-kB inhibitor. On the other hand, the group B drugs were not inhibited by NF-kB inhibitors or geldanamycin but their e ect was abolished by the src inhibitor PP2. Group C drugs depended on both pathways. 5 In terms of PGE 2 generation, there is clear evidence of two entirely separate mechanisms of glucocorticoid action, one of which correlates with NF-kB mediated genomic actions whilst the other, depends upon rapid e ects on a cell signalling system which does not require dissociation of GR. The implications for these ®ndings are discussed.

Rapid Effects of Dexamethasone on Intracellular pH and Na+/H+ Exchanger Activity in Human Bronchial Epithelial Cells

“…However, the higher potency of fluticasone compared with aldosterone on pH i regulation after an acid load suggests the involvement of a receptor selective for glucocorticoids but distinct from the nuclear glucocorticoid receptor responsible for the genomic action of glucocorticoids. These results are consistent with other rapid responses to glucocorticoids that do not involve the "classical" nuclear receptor (6,10,47). The sensitivity of the response to pertussis toxin may indicate the involvement of a novel membrane-associated receptor, and the identification of membrane-binding sites for glucocorticoids supports this hypothesis (48 -50).…”

Monocyte chemotactic protein-1 in the migration of differentiated leukaemic cells toward alveolar epithelial cells

“…These data further support the following theories: 1) MCP-1 secreted by alveolar epithelial cells is important in the regulation of transmigration of differentiated APL cells into the alveolar spaces; 2) the therapeutic effect of DEX on the transmigration of ATRA-treated APL cells is actually mediated, in part, through its inhibitory action on MCP-1 secretion in A549 cells, but not in APL cells; and 3) lung epithelial cells are also susceptible to ATRA and DEX treatment. The inhibitory effect of DEX on the MCP-1 secretion from the alveolar epithelial cells has previously been reported [17], and its underlying mechanism is likely to be mediated by glucocorticoid receptor through a novel mechanism in which the glucocorticoid receptor binds directly to MCP-1 mRNA and facilitates its degradation [18,19]. However, glucocorticoid binding and cellular glucocorticoid receptor levels were not changed in the APL cells during the process of ATRA-induced granulocytic differentiation [20].…”

Metabolic comorbidities in Cushing's syndrome

“…Fluorinated steroids (such as dexamethasone or betamethasone) cause myopathy more frequently than non-fluorinated agents (such as prednisolone and hydrocortisone) (211). The reason why fluorinated agents are more frequently associated to myopathy is not clear, but it could be speculated that different GCs exert different genomic and non-genomic actions and impact on different signalling pathways, having different anti-inflammatory or anti-proliferative effects, with consequent different metabolic outcomes (212). Chronic GC excess generally has a more prominent effect on the proximal muscles (213).…”