Thiazolidinediones are partial agonists for the glucocorticoid receptor.
Although thiazolidinediones were designed as specific peroxisome proliferator-activated receptor (PPAR)-gamma-ligands, there is evidence for some off-target effects mediated by a non-PPARgamma mechanism. Previously we have shown that rosiglitazone has antiinflammatory actions not explicable by activation of PPARgamma,but possibly by the glucocorticoid receptor (GR). Rosiglitazone induces nuclear translocation both of GR-green fluorescent protein, and endogenous GR in HeLa and U20S cells but with slower kinetics than dexamethasone. Rosiglitazone also induces GR phosphorylation (Ser211), a GR ligand-binding-specific effect. Rosiglitazone drives luciferase expression from a simple glucocorticoid-response element containing reporter gene in a GR-dependent manner (EC50 4 microm), with a similar amplitude response to the partial GR agonist RU486. Rosiglitazone also inhibits dexamethasone-driven reporter gene activity (IC50 2.9 microm) in a similar fashion to RU486, suggesting partial agonist activity. Importantly we demonstrate a similar effect in PPARgamma-null cells, suggesting both GR dependence and PPARgamma independence. Rosiglitazone also activates a GAL4-GR chimera, driving a upstream activating sequence promoter, demonstrating DNA template sequence independence and furthermore enhanced steroid receptor coactivator-1-GR interaction, measured by a mammalian two-hybrid assay. Both ciglitazone and pioglitazone, structurally related to rosiglitazone, show similar effects on the GR. The antiproliferative effect of rosiglitazone is increased in U20S cells that overexpress GR, suggesting a biologically important GR-dependent component of rosiglitazone action. Rosiglitazone is a partial GR agonist, affecting GR activation and trafficking to influence engagement of target genes and affect cell function. This novel mode of action may explain some off-target effects observed in vivo. Additionally, antagonism of glucocorticoid action may contribute to the antidiabetic actions of rosiglitazone.
Matthews
L
L
Endocrine Sciences Research Group, Division of Cardiovascular and Endocrine Science, University of Manchester, Manchester M13 9PT, United Kingdom.
Berry
A
A
Tersigni
M
M
D'Acquisto
F
F
Ianaro
A
A
Ray
D
D
D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D017930:Genes, Reporter; D006367:HeLa Cells; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms; D015735:Mifepristone / Q000494:pharmacology; D047495:PPAR gamma / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014162:Transfection
D006727:Hormone Antagonists; D047495:PPAR gamma; D011965:Receptors, Glucocorticoid; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D015735:Mifepristone; D003907:Dexamethasone; D008156:Luciferases
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