Dec 29, 2007 - 7:43 pm
Might be of interest to glioma patients. This suggest the drug mifepristone (also called RU486) is transcriptionally active so could be used in combination with chemo/radiation to improve efficacy of those treatments:
Implication of glucocorticoid receptors in the stimulation of human glioma cell proliferation by dexamethasone.
....Dexamethasone is frequently used in the therapy of brain tumor patients. We investigated the effect of dexamethasone on the proliferation of three short-term and four established human glioma cell lines in vitro, using a microculture tetrazolium assay to determine growth rates. In one short-term culture and in one established cell line dexamethasone consistently stimulated the proliferation in a concentration-dependent way. The proliferation was maximally enhanced at a concentration of approximately 0.1 microM. In these two cell lines a relatively high level of glucocorticoid receptors was present, whereas low levels of glucocorticoid receptors were found in the other cell lines. In addition, we demonstrated that the stimulatory effects of dexamethasone on the proliferation of the glioma cell lines can be antagonized by the antiglucocorticoid RU38486. The results demonstrate unequivocally that the glucocorticoid receptor plays a role in the growth stimulating effect of dexamethasone.
2007: Human Glucocorticoid Receptor â Binds RU-486 and Is Transcriptionally Active
Human glucocorticoid receptor (hGR) is expressed as two alternately spliced C-terminal isoforms, á and â. In contrast to the canonical hGRá, hGRâ is a nucleus-localized orphan receptor thought not to bind ligand and not to affect gene transcription other than by acting as a dominant negative to hGRá. Here we used confocal microscopy to examine the cellular localization of transiently expressed fluorescent protein-tagged hGRâ in COS-1 and U-2 OS cells. Surprisingly, yellow fluorescent protein (YFP)-hGRâ was predominantly located in the cytoplasm and translocated to the nucleus following application of the glucocorticoid antagonist RU-486. This effect of RU-486 was confirmed with transiently expressed wild-type hGRâ. Confocal microscopy of coexpressed YFP-hGRâ and cyan fluorescent protein-hGRá in COS-1 cells indicated that the receptors move into the nucleus independently. Using a ligand binding assay, we confirmed that hGRâ bound RU-486 but not the hGRá ligand dexamethasone. Examination of the cellular localization of YFP-hGRâ in response to a series of 57 related compounds indicated that RU-486 is thus far the only identified ligand that interacts with hGRâ. The selective interaction of RU-486 with hGRâ was also supported by molecular modeling and computational docking studies. Interestingly, microarray analysis indicates that hGRâ, expressed in the absence of hGRá, can regulate gene expression and furthermore that occupation of hGRâ with the antagonist RU-486 diminishes that capacity despite the lack of helix 12 in the ligand binding domain......
....When used as an abortifacient, RU-486 is administered as a single 600-mg dose (31). Other uses for this potent antiprogestin, antiglucocorticoid agent are also being explored, which would likely entail different doses and administration plans (31). Due to its low rate of metabolic clearance in humans, even a single 100-mg dose of RU-486 persists at micromolar concentrations in the blood up to 72 h after administration (11). Thus, although the affinity of hGRâ for RU-486 is relatively low, it is possible that standard use of this drug results in modification of the activity of endogenous hGRâ. Furthermore, our demonstration of the ability of hGRâ to bind a ligand suggests that it may be possible to design other ligands with higher affinity for this receptor. Taken together, this work suggests that hGRâ may have a more important physiological role than has previously been thought, both as an endogenous manipulator of gene expression and as a pharmaceutical target.(more detail via link above)