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- DOI: 10.1210/en.2008-0196
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Thiazolidinediones are partial agonists for the glucocorticoid receptor.
Matthews L, Berry A, Tersigni M, D'Acquisto F, Ianaro A, Ray DW
Endocrinology. 2009;150:75-86.
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Full-text held externally
- DOI: 10.1210/en.2008-0196
Abstract
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.
Keyword(s)
Cell Line, Tumor; Enzyme Activation; Genes, Reporter; Hela Cells; Humans; Lung Neoplasms; Transfection; agonists: Receptors, Glucocorticoid; antagonists & inhibitors: Dexamethasone; drug effects: Cell Division; genetics: Luciferases; pharmacology: Hormone Antagonists; pharmacology: Mifepristone; pharmacology: Thiazolidinediones; physiology: PPAR gamma