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Published on: November 3, 2013
PI3K inhibitors protect against glucocorticoid-induced skin atrophy
Shivani Agarwal1, Salida Mirzoeva1, Ben Readhead2
1Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Background:
Skin atrophy is a major adverse effect of topical glucocorticoids. We recently reported that REDD1 (regulated in development and DNA damage 1) and FKBP51 (FK506 binding protein 5), negative regulators of mTOR/Akt signaling, are induced by glucocorticoids in mouse and human skin and are central drivers of steroid skin atrophy. Thus, we hypothesized that REDD1/FKBP51 inhibitors could protect skin against catabolic effects of glucocorticoids.
Methods:
Using drug repurposing approach, we screened LINCS library (http://lincsproject.org/LINCS/) to identify repressors of REDD1/FKBP51 expression. Candidate compounds were tested for their ability to inhibit glucocorticoid-induced REDD1/FKBP51 expression in human primary/immortalized keratinocytes and in mouse skin. Reporter gene expression, microarray, and chromatin immunoprecipitation were employed to evaluate effect of these inhibitors on the glucocorticoid receptor (GR) signaling.
Findings:
Bioinformatics analysis unexpectedly identified phosphoinositide-3-kinase (PI3K)/mTOR/Akt inhibitors as a pharmacological class of REDD1/FKBP51 repressors. Selected PI3K/mTOR/Akt inhibitors-Wortmannin (WM), LY294002, AZD8055, and two others indeed blocked REDD1/FKBP51expression in human keratinocytes. PI3K/mTOR/Akt inhibitors also modified global effect of glucocorticoids on trascriptome, shifting it towards therapeutically important transrepression; negatively impacted GR phosphorylation; nuclear translocation; and GR loading on REDD1/FKBP51 gene promoters. Further, topical application of LY294002 together with glucocorticoid fluocinolone acetonide (FA) protected mice against FA-induced proliferative block and skin atrophy but did not alter the anti-inflammatory activity of FA in ear edema test.
Interpretation:
Our results built a strong foundation for development of safer GR-targeted therapies for inflammatory skin diseases using combination of glucocorticoids with PI3K/mTOR/Akt inhibitors. FUND: Work is supported by NIH grants R01GM112945, R01AI125366, and HESI-THRIVE foundation.
Insights
Glucocorticoids cause skin atrophy by increasing REDD1/FKBP51. Inhibiting PI3K/mTOR/Akt blocked this effect, protecting skin without reducing anti-inflammatory benefits, paving the way for safer therapies.
Area of Science:
- Dermatology
- Molecular Biology
- Pharmacology
Background:
- Topical glucocorticoids induce skin atrophy, a significant adverse effect.
- REDD1 and FKBP51, negative regulators of mTOR/Akt signaling, are key mediators of glucocorticoid-induced skin atrophy.
- Inhibiting REDD1/FKBP51 presents a potential therapeutic strategy against steroid-induced skin atrophy.
Purpose of the Study:
- To identify inhibitors of REDD1/FKBP51 expression.
- To investigate the potential of these inhibitors in preventing glucocorticoid-induced skin atrophy.
- To evaluate the impact of these inhibitors on glucocorticoid receptor (GR) signaling.
Main Methods:
- Drug repurposing screen of the LINCS library to identify REDD1/FKBP51 repressors.
- In vitro testing in human keratinocytes and in vivo studies in mouse skin.
- Assays included reporter gene expression, microarray, chromatin immunoprecipitation, and ear edema tests.
Main Results:
- Unexpectedly identified PI3K/mTOR/Akt inhibitors as repressors of REDD1/FKBP51.
- Selected PI3K/mTOR/Akt inhibitors blocked REDD1/FKBP51 expression in human keratinocytes.
- Topical application of a PI3K/mTOR/Akt inhibitor protected mice against skin atrophy without compromising anti-inflammatory effects.
Conclusions:
- PI3K/mTOR/Akt inhibitors are a novel class of REDD1/FKBP51 repressors.
- Combination therapy with glucocorticoids and PI3K/mTOR/Akt inhibitors offers a promising approach for safer GR-targeted treatments.
- This strategy could lead to improved therapies for inflammatory skin diseases with reduced side effects.
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