Abstract
Glucocorticoids have excellent therapeutic properties; however, they cause significant adverse atrophogenic effects. The mTORC1 inhibitor REDD1 has been recently identified as a key mediator of glucocorticoid-induced atrophy. We performed computational screening of a connectivity map database to identify putative REDD1 inhibitors. The top selected candidates included rapamycin, which was unexpected because it inhibits pro-proliferative mTOR signaling. Indeed, rapamycin inhibited REDD1 induction by glucocorticoids dexamethasone, clobetasol propionate, and fluocinolone acetonide in keratinocytes, lymphoid cells, and mouse skin. We also showed blunting of glucocorticoid-induced REDD1 induction by either catalytic inhibitor of mTORC1/2 (OSI-027) or genetic inhibition of mTORC1, highlighting role of mTOR in glucocorticoid receptor signaling. Moreover, rapamycin inhibited glucocorticoid receptor phosphorylation, nuclear translocation, and loading on glucocorticoid-responsive elements in REDD1 promoter. Using microarrays, we quantified a global effect of rapamycin on gene expression regulation by fluocinolone acetonide in human keratinocytes. Rapamycin inhibited activation of glucocorticoid receptor target genes yet enhanced the repression of pro-proliferative and proinflammatory genes. Remarkably, rapamycin protected skin against glucocorticoid-induced atrophy but had no effect on the glucocorticoid anti-inflammatory activity in different invivo models, suggesting the clinical potential of combining rapamycin with glucocorticoids for the treatment of inflammatory diseases.
Highlights
Glucocorticoids are among the most effective antiinflammatory and anti-lymphoma drugs (Lesovaya et al, 2015)
Selection of rapamycin as a prospective REDD1 inhibitor Because pharmacological REDD1 inhibitors are not known, we used a modified connectivity mapping approach and screened a CMAP library representing molecular signatures of approximately 1,300 US Food and Drug Administrationapproved and experimental drugs tested in human cancer cells to repurpose them for cancer treatment (Lamb et al, 2006)
MTOR inhibitors rapamycin and OSI-027 down-regulate REDD1 expression induced by diverse glucocorticoids Rapamycin effects were tested in keratinocytes and lymphoid cells (CEM), because glucocorticoid effects in lymphocytes are critically important for steroid anti-inflammatory activity
Summary
Glucocorticoids are among the most effective antiinflammatory and anti-lymphoma drugs (Lesovaya et al, 2015). Chronic treatment with glucocorticoids results in multiple metabolic and atrophic adverse effects that reflect glucocorticoid catabolic activity (De Bosscher et al, 2010; Lesovaya et al, 2015). Blokhin Cancer Research Center, Moscow, Russia; 2I.P. Pavlov Ryazan State Medical University, Ryazan, Russia; 3Department of Dermatology, Northwestern University, Chicago, Illinois, USA; 4Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA; 5Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA; 6Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA; and 7Department of Medicine, Jesse Brown VA Medical Center, Chicago, Illinois, USA
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
