PI3K inhibitors protect against glucocorticoid-induced skin atrophy.
EBioMedicine
; 41: 526-537, 2019 Mar.
Article
em En
| MEDLINE
| ID: mdl-30737086
ABSTRACT
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.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Pele
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Inibidores de Proteínas Quinases
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Inibidores de Fosfoinositídeo-3 Quinase
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Glucocorticoides
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article